Substituted benzazoles and methods of their use as inhibitors of Raf kinase

ABSTRACT

New substituted benz-azole compounds, compositions and methods of inhibition of Raf kinase activity in a human or animal subject are provided. The new compounds compositions may be used either alone or in combination with at least one additional agent for the treatment of a Raf kinase mediated disorder, such as cancer.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application is a continuation-in-part of U.S. applicationSer. No. 10/405,945 filed Mar. 31, 2003, which is based on U.S.provisional application Serial No. 60/369,066 filed Mar. 29, 2002.

FIELD OF THE INVENTION

[0002] The present invention relates to new substituted benz-azole-likecompounds and pharmaceutically acceptable salts, esters or prodrugsthereof, compositions of the new compounds together withpharmaceutically acceptable carriers, and uses of the new compounds,either alone or in combination with at least one additional therapeuticagent, in the prophylaxis or treatment of cancer.

BACKGROUND OF THE INVENTION

[0003] The Raf serine/threonine kinases are essential components of theRas/Mitogen-Activated Protein Kinase (MAPK) signaling module thatcontrols a complex transcriptional program in response to externalcellular stimuli. Raf genes code for highly conservedserine-threonine-specific protein kinases which are known to bind to theras oncogene. They are part of a signal transduction pathway believed toconsist of receptor tyrosine kinases, p21 ras, Raf protein kinases, Mek1(ERK activator or MAPKK) kinases and ERK (MAPK) kinases, whichultimately phosphorylate transcription factors. In this pathway Rafkinases are activated by Ras and phosphorylate and activate two isoformsof Mitogen-Activated Protein Kinase Kinase (called Mek1 and Mek2), thatare dual specificity threonine/tyrosine kinases. Both Mek isoformsactivate Mitogen Activated Kinases 1 and 2 (MAPK, also calledExtracellular Ligand Regulated Kinase 1 and 2 or Erk1 and Erk2). TheMAPKs phosphorylate many substrates including transcription factors andin so doing set up their transcriptional program. Raf kinaseparticipation in the Ras/MAPK pathway influences and regulates manycellular functions such as proliferation, differentiation, survival,oncogenic transformation and apoptosis.

[0004] Both the essential role and the position of Raf in many signalingpathways have been demonstrated from studies using deregulated anddominant inhibitory Raf mutants in mammalian cells as well as fromstudies employing biochemical and genetic techniques model organisms. Inmany cases, the activation of Raf by receptors that stimulate cellulartyrosine phosphorylation is dependent on the activity of Ras, indicatingthat Ras functions upstream of Raf. Upon activation, Raf-1 thenphosphorylates and activates Mek1, resulting in the propagation of thesignal to downstream effectors, such as MAPK (mitogen-activated proteinkinase) (Crews et al. (1993) Cell 74:215). The Raf serine/threoninekinases are considered to be the primary Ras effectors involved in theproliferation of animal cells (Avruch et al. (1994) Trends Biochem. Sci.19:279).

[0005] Raf kinase has three distinct isoforms, Raf-1 (c-Raf), A-Raf, andB-Raf, distinguished by their ability to interact with Ras, to activateMAPK kinase pathway, tissue distribution and sub-cellular localization(Marias et. Al., Biochem. J. 351: 289-305, 2000; Weber et. al., Oncogene19:169-176, 2000; Pritchard et. al., Mol. Cell. Biol. 15:6430-6442,1995). Raf kinases are activated by Ras and phosphorylate and activatetwo isoforms of Mitogen-Activated Protein Kinase Kinase (called Mek1 andMek2) that are dual specificity threonine/tyrosine kinases. Both Mekisoforms activate Mitogen Activated Kinases 1 and 2 (MAPK, also calledExtracellular Ligand Regulated Kinase 1 and 2 or Erk1 and Erk2). TheMAPKs phosphorylate many substrates including cytosolic proteins and ETSfamily of transcription factors. Raf kinase participation in theRas/MAPK pathway influences and regulates many cellular functions suchas proliferation, differentiation, survival, cell cycle progression andapoptosis.

[0006] Activating mutation of one of the Ras genes can be seen in ˜20%of all tumors and the Raf/MEK/ERK pathway is activated in ˜30% of alltumors (Bos et. al., Cancer Res. 49:4682-4689, 1989) (Hoshino et. al.,Oncogene 18:813-822, 1999). Recent studies have shown that B-Rafmutation in the skin nevi is a critical step in the initiation ofmelanocytic neoplasia (Pollock et. al., Nature Genetics 25: 1-2, 2002).Furthermore, most recent studies have emerged that activating mutationin the kinase domain of B-Raf occurs in ˜66% of melanomas, 12% of coloncarcinoma and 14% of liver cancer (Davies et. al., Nature 417:949-954,2002) (Yuen et. al., Cancer Research 62:6451-6455, 2002) (Brose et. al.,Cancer Research 62:6997-7000, 2002).

[0007] Inhibitors of Raf/MEK/ERK pathway at the level of Raf kinases canpotentially be effective as therapeutic agents against tumors withover-expressed or mutated receptor tyrosine kinases, activatedintracellular tyrosine kinases, tumors with aberrantly expressed Grb2(an adapter protein that allows stimulation of Ras by the Sos exchangefactor) as well as tumors harboring activating mutations of Raf itself.In the early clinical trails inhibitor of Raf-1 kinase that also inhibitB-Raf have shown promise as therapeutic agents in cancer therapy (Crump,Current Pharmaceutical Design 8: 2243-2248, 2002; Sebastien et. al.,Current Pharmaceutical Design 8: 2249-2253, 2002).

[0008] Disruption of Raf expression in cell lines through theapplication of RNA antisense technology has been shown to suppress bothRas and Raf-mediated tumorigenicity (Kolch et al., Nature 349:416-428,1991; Monia et al., Nature Medicine 2(6):668-675, 1996).

[0009] Several Raf kinase inhibitors have been described as exhibitingefficacy in inhibiting tumor cell proliferation in vitro and/or in vivoassays (see, e.g., U.S. Pat. Nos. 6,391,636, 6,358,932, 6,037,136,5,717,100, 6,458,813, 6,204,467, and 6,268,391). Other patents andpatent applications suggest the use of Raf kinase inhibitors fortreating leukemia (see, e.g., U.S. Pat. Nos. 6,268,391, and 6,204,467,and published U.S. patent application Ser. Nos. 20,020,137,774;20,020,082,192; 20,010,016,194; and 20,010,006,975), or for treatingbreast cancer (see, e.g., U.S. Pat. Nos. 6,358,932, 5,717,100,6,458,813, 6,268,391, and 6,204,467, and published U.S. patentapplication Ser. No. 20,010,014,679).

SUMMARY OF THE INVENTION

[0010] New substituted benz-azole compounds and pharmaceuticallyacceptable salts thereof or esters having a solubility enhancingmoieties or prodrugs thereof are provided of the formula (I):

[0011] wherein, X₁ and X₂ are independently selected from ═N—, —NR₄—,—O— or —S—, provided that if X₁ is —NR₄—, —O— or —S—, then X₂ is ═N—, orif X₂ is —NR₄—, —O— or —S—, then X₂ is ═N—, and both X₁ and X₂ are not═N—;

[0012] Y is O or S;

[0013] A₁ is substituted or unsubstituted alkyl, cycloalkyl,heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl,heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl,cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,biarylalkyl, or heteroarylarylalkyl;

[0014] A₂ is substituted or unsubstituted heteroaryl;

[0015] R₁ is O or H, and R₂ is NR₅R₆ or hydroxyl; or R₁ is takentogether with R₂ to form a substituted or unsubstituted heterocycloalkylor heteroaryl group; wherein, the dashed line represents a single ordouble bond;

[0016] R₃ is hydrogen, halogen, loweralkyl, or loweralkoxy;

[0017] R₄ is hydrogen, hydroxyl, alkylamino, dialkylamino or alkyl;

[0018] R₅ and R₆ are independently selected from hydrogen, andsubstituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl,acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkyloxyalkylheterocyclo, and heteroarylalkyl; or R₅ and R₆ are takentogether to form substituted or unsubstituted heterocyclo or heteroaryl;and

[0019] R₇ is loweralkyl;

[0020] or a pharmaceutically acceptable salt, ester or prodrug thereof.

[0021] In other embodiments, new substituted benz-azole compounds areprovided of the formula (II):

[0022] wherein and Y, Ar₁, Ar₂, R₁, R₂, R₃ and R₄ are as defined above;or

[0023] a pharmaceutically acceptable salt, ester or prodrug thereof.

[0024] In other embodiments, new substituted benz-azole compounds areprovided of the formula (III):

[0025] wherein X₁, Ar₁, Ar₂, R₁, R₂ and R₃ are as defined above; and

[0026] the pharmaceutically acceptable salts, esters, tautomers andprodrugs thereof.

[0027] In other embodiments, new substituted benz-azole compounds areprovided of the formula (IV):

[0028] wherein X₁, Y, Ar₁, R₁, R₂ and R₃ are as defined above; and

[0029] the pharmaceutically acceptable salts, esters, tautomers andprodrugs thereof.

[0030] In yet other embodiments, new substituted benz-azole compoundsare provided of the formula (V):

[0031] wherein X₁, Ar₁, R₁, R₂ and R₃ are as defined above; and

[0032] the pharmaceutically acceptable salts, esters, tautomers andprodrugs thereof.

[0033] In other aspects, the present invention provides methods fortreating Raf related disorders in a human or animal subject in need ofsuch treatment comprising administering to said subject an amount of acompound of formula (I), (II), (III), (IV) or (V) effective to reduce orprevent tumor growth in the subject.

[0034] In yet other aspects, the present invention provides methods fortreating Raf related disorders in a human or animal subject in need ofsuch treatment comprising administering to said subject an amount of acompound of formula (I), (II), (III), (IV) or (V) effective to reduce orprevent tumor growth in the subject in combination with at least oneadditional agent for the treatment of cancer.

[0035] In yet other aspects, the present invention provides therapeuticcompositions comprising at least one compound of formula (I), (II),(III), (IV) or (V) in combination with one or more additional agents forthe treatment of cancer, as are commonly employed in cancer therapy.

[0036] The compounds of the invention are useful in the treatment ofcancers, including carcinomas (e.g., of the lungs, pancreas, thyroid,bladder or colon), myeloid disorders (e.g., myeloid leukemia) andadenomas (e.g., villous colon adenoma).

[0037] The invention farther provides compositions, methods of use, andmethods of manufacture as described in the detailed description of theinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0038] In accordance with one aspect of the present invention, newsubstituted benz-azole compounds and pharmaceutically acceptable salts,esters or prodrugs thereof are provided of the formula (I):

[0039] wherein, X₁ and X₂ are independently selected from ═N—, —NR₄—,—O— or —S—, provided that if X₁ is —NR₄—, —O— or —S—, then X₂ is ═N—, orif X₂ is —NR₄—, —O— or —S—, then X₂ is ═N—, and both X₁ and X₂ are not═N—;

[0040] Y is O or S;

[0041] A₁ is substituted or unsubstituted alkyl, cycloalkyl,heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl,heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl,cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,biarylalkyl, or heteroarylarylalkyl;

[0042] A₂ is substituted or unsubstituted heteroaryl;

[0043] R₁ is O or H, and R₂ is NR₅R₆ or hydroxyl; or R₁ is takentogether with R₂ to form a substituted or unsubstituted heterocycloalkylor heteroaryl group; wherein, the dashed line represents a single ordouble bond;

[0044] R₃ is hydrogen, halogen, loweralkyl, or loweralkoxy;

[0045] R₄ is hydrogen, hydroxyl, alkylamino, dialkylamino or alkyl;

[0046] R₅ and R6 are independently selected from hydrogen, andsubstituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl,acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkyloxyalkylheterocyclo, and heteroarylalkyl; or R₅ and R₆ are takentogether to form substituted or unsubstituted heterocyclo or heteroaryl;and

[0047] R₇ is loweralkyl;

[0048] or a pharmaceutically acceptable salt, ester or prodrug thereof.

[0049] In other embodiments, new substituted benz-azole compounds areprovided of the formula (II):

[0050] wherein and Y, Ar₁, Ar₂, R₁, R₂, R₃ and R₄ are as defined above;or

[0051] a pharmaceutically acceptable salt, ester or prodrug thereof.

[0052] In other embodiments, new substituted benz-azole compounds areprovided of the formula (III):

[0053] wherein X₁, Ar₁, Ar₂, R₁, R₂ and R₃ are as defined above; and

[0054] the pharmaceutically acceptable salts, esters, tautomers andprodrugs thereof.

[0055] In other embodiments, new substituted benz-azole compounds areprovided of the formula (IV):

[0056] wherein X₁, Y, Ar₁, R₁, R₂ and R₃ are as defined above; and

[0057] the pharmaceutically acceptable salts, esters, tautomers andprodrugs thereof.

[0058] In yet other embodiments, new substituted benz-azole compoundsare provided of the formula (V):

[0059] wherein X₁, Ar₁, R₁, R₂ and R₃ are as defined above; and

[0060] the pharmaceutically acceptable salts, esters, tautomers andprodrugs thereof.

[0061] In another aspect, the present invention provides methods oftreating human or animal subjects suffering from a Raf related disorder,such as cancer. Thus, the present invention provides methods of treatinga human or animal subject in need of such treatment comprisingadministering to the subject a therapeutically effective amount of acompound of formula I, II, III, IV or V above, either alone or incombination with other anticancer agents.

[0062] In other aspects, the present invention provides methods fortreating Raf related disorders in a human or animal subject in need ofsuch treatment comprising administering to said subject an amount of acompound of formula (I), (II), (III), (IV) or (V) effective to reduce orprevent tumor growth in the subject.

[0063] In yet other aspects, the present invention provides methods fortreating Raf related disorders in a human or animal subject in need ofsuch treatment comprising administering to said subject an amount of acompound of formula (I), (II), (III), (IV) or (V) effective to reduce orprevent tumor growth in the subject in combination with at least oneadditional agent for the treatment of cancer. A number of suitableanticancer agents to be used as combination therapeutics arecontemplated for use in the methods of the present invention. Indeed,the present invention contemplates, but is not limited to,administration of numerous anticancer agents such as: agents that induceapoptosis; polynucleotides (e.g., ribozymes); polypeptides (e.g.,enzymes); drugs; biological mimetics; alkaloids; alkylating agents;antitumor antibiotics; antimetabolites; hormones; platinum compounds;monoclonal antibodies conjugated with anticancer drugs, toxins, and/orradionuclides; biological response modifiers (e.g. interferons [e.g.IFN-a, etc.] and interleukins [e.g. IL-2, etc.], etc.); adoptiveimmunotherapy agents; hematopoietic growth factors; agents that inducetumor cell differentiation (e.g. all-trans-retinoic acid, etc.); genetherapy reagents; antisense therapy reagents and nucleotides; tumorvaccines; inhibitors of angiogenesis, and the like. Numerous otherexamples of chemotherapeutic compounds and anticancer therapies suitablefor coadministration with the disclosed compounds of formula (I), (II),(III), (IV) or (V) are known to those skilled in the art.

[0064] In preferred embodiments, anticancer agents to be used incombination with compounds of the present invention comprise agents thatinduce or stimulate apoptosis. Agents that induce apoptosis include, butare not limited to, radiation (e.g., W); kinase inhibitors (e.g.,Epidermal Growth Factor Receptor [EGFR] kinase inhibitor, VascularGrowth Factor Receptor [VGFR] kinase inhibitor, Fibroblast Growth FactorReceptor [FGFR] kinase inhibitor, Platelet-derived Growth FactorReceptor [PGFR] I kinase inhibitor, and Bcr-Abl kinase inhibitors suchas STI-571, Gleevec, and Glivec]); antisense molecules; antibodies[e.g., Herceptin and Rituxan]; anti-estrogens [e.g., raloxifene andtamoxifen]; anti-androgens [e.g., flutamide, bicalutamide, finasteride,amino-glutethamide, ketoconazole, and corticosteroids]; cyclooxygenase 2(COX-2) inhibitors [e.g., Celecoxib, meloxicam, NS-398, andnon-steroidal antiinflammatory drugs (NSAIDs)]; and cancerchemotherapeutic drugs [e.g., irinotecan (Camptosar), CPT-11,fludarabine (Fludara), dacarbazine (DTIC), dexamethasone, mitoxantrone,Mylotarg, VP-16, cisplatinum, 5-FU, Doxrubicin, Taxotere or taxol];cellular signaling molecules; ceramides and cytokines; and staurosprine,and the like.

[0065] In other aspects, the present invention provides pharmaceuticalcompositions comprising at least one compound of formula I, II, III, IVor V together with a pharmaceutically acceptable carrier suitable foradministration to a human or animal subject, either alone or togetherwith other anticancer agents.

[0066] In other aspects, the present invention provides methods ofmanufacture of compounds of formula I, II, III, IV or V as describedherein.

[0067] In yet other aspects, the present invention provides compoundswhich are inhibitors of the enzyme raf kinase. Since the enzyme is adownstream effector of p21^(ras), the instant inhibitors are useful inpharmaceutical compositions for human or veterinary use where inhibitionof the raf kinase pathway is indicated, e.g., in the treatment of tumorsand/or cancerous cell growth mediated by raf kinase. In particular, thecompounds are useful in the treatment of human or animal, e.g., murinecancer, since the progression of these cancers is dependent upon the rasprotein signal transduction cascade and therefore is susceptible totreatment by interruption of the cascade by inhibiting raf kinaseactivity. Accordingly, the compounds of the invention are useful intreating solid cancers, such as, for example, carcinomas (e.g., of thelungs, pancreas, thyroid, bladder or colon, myeloid disorders (e.g.,myeloid leukemia) or adenomas (e.g., villous colon adenoma).

[0068] “Raf inhibitor” is used herein to refer to a compound thatexhibits an IC₅₀ with respect to Raf Kinase activity of no more thanabout 100 μM and more typically not more than about 50 μM, as measuredin the Raf/Mek Filtration Assay described generally hereinbelow.Preferred isoforms of Raf Kinase in which the compounds of the presentinvention will be shown to inhibit, include A-Raf, B-Raf, and C-Raf(Raf-1). “IC₅₀” is that concentration of inhibitor which reduces theactivity of an enzyme (e.g., Raf kinase) to half-maximal level.Representative compounds of the present invention have been discoveredto exhibit inhibitory activity against Raf. Compounds of the presentinvention preferably exhibit an IC₅₀ with respect to Raf of no more thanabout 10 μM, more preferably, no more than about 5 μM, even morepreferably not more than about 1 μM, and most preferably, not more thanabout 200 nM, as measured in the Raf kinase assays described herein.

[0069] As used herein, the term “benz-azoles” includes benzimidazoles,benzothiazoles and benzoxazoles.

[0070] The phrase “alkyl” refers to alkyl groups that do not containheteroatoms. Thus the phrase includes straight chain alkyl groups suchas methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl,decyl, undecyl, dodecyl and the like. The phrase also includes branchedchain isomers of straight chain alkyl groups, including but not limitedto, the following which are provided by way of example: —CH(CH₃)₂,—CH(CH₃)(CH₂CH₃), —CH(CH₂CH₃)₂, —C(CH₃)₃, —C(CH₂CH₃)₃, —CH₂CH(CH₃)₂,—CH₂CH(CH₃)(CH₂CH₃), —CH₂CH(CH₂CH₃)₂, —CH₂C(CH₃)₃, —CH₂C(CH₂CH₃)₃,—CH(CH₃)CH(CH₃)(CH₂CH₃), —CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH(CH₃)(CH₂CH₃),—CH₂CH₂CH(CH₂CH₃)₂, —CH₂CH₂C(CH₃)₃, —CH₂CH₂C(CH₂CH₃)₃, —CH(CH₃CH₂.CH(CH₃)₂, —CH(CH₃)CH(CH₃)CH(CH₃)₂, —CH(CH₂CH₃)CH(CH₃)CH(CH₃)(CH₂CH₃),and others. The phrase also includes cyclic alkyl groups such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl and such rings substituted with straight and branched chainalkyl groups as defined above. Thus the phrase alkyl groups includesprimary alkyl groups, secondary alkyl groups, and tertiary alkyl groups.Preferred alkyl groups include straight and branched chain alkyl groupsand cyclic alkyl groups having 1 to 12 carbon atoms.

[0071] As used herein “loweralkyl” includes-both substituted orunsubstituted straight or branched chain alkyl groups having from 1 to 6carbon atoms. Representative loweralkyl groups include, for example,methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl,trifluoromethyl, pentafluoroethyl and the like. Loweralkyl groups may besubstituted, such as with halo, hydroxy, amino, nitro and/or cyanogroups, and the like. Representative of halo-substituted andhydroxy-substituted loweralkyl include chloromethyl, trichloromethyl,chloroethyl, hydroxyethyl, and the like. Other suitable substitutedloweralkyl moieties include, for example, aralkyl, aminoalkyl,aminoaralkyl, carbonylaminoalkyl, alkylcarbonylaminoalkyl,arylcarbonylaminoalkyl, aralkylcarbonyl-aminoalkyl, aminoalkoxyalkyl andarylaminoalkyl. “Loweralkoxy” as used herein refers to RO— wherein R isloweralkyl. Representative examples of loweralkoxy groups includemethoxy, ethoxy, t-butoxy, trifluoromethoxy and the like.

[0072] As used herein, the term “halogen” or “halo” refers to chloro,bromo, fluoro and iodo groups. “Haloalkyl” refers to an alkyl radicalsubstituted with one or more halogen atoms. The term “haloloweralkyl”refers to a loweralkyl radical substituted with one or more halogenatoms. The term “haloalkoxy” refers to an alkoxy radical substitutedwith one or more halogen atoms. The term “haloloweralkoxy” refers to aloweralkoxy radical substituted with one or more halogen atoms. “Amino”refers herein to the group —NH₂. The term “alkylamino” refers herein tothe group —NRR′ where R and R′ are each independently selected fromhydrogen or a lower alkyl. The term “arylamino” refers herein to thegroup —NRR′ where R is aryl and R′ is hydrogen, a lower alkyl, or anaryl. The term “aralkylamino” refers herein to the group —NRR′ where Ris a lower aralkyl and R′ is hydrogen, a loweralkyl, an aryl, or aloweraralkyl.

[0073] The term “alkoxyalkyl” refers to the group -alk₁-O-alk₂ wherealk₁ is alkyl or alkenyl, and alk₂ is alkyl or alkenyl. The term“loweralkoxyalkyl” refers to an alkoxyalkyl where alk₁ is loweralkyl orloweralkenyl, and alk₂ is loweralkyl or loweralkenyl. The term“aryloxyalkyl” refers to the group -alkyl-O-aryl. The term“aralkoxyalkyl” refers to the group -alkylenyl-O-aralkyl, where aralkylis a loweraralkyl.

[0074] The term “alkoxyalkylamino” refers herein to the group—NR-(alkoxyalkyl), where R is typically hydrogen, loweraralkyl, orloweralkyl. The term “aminoloweralkoxyalkyl” refers herein to anaminoalkoxyalkyl in which the alkoxyalkyl is a loweralkoxyalkyl.

[0075] The term “aminocarbonyl” refers herein to the group —C(O)—NH₂.“Substituted aminocarbonyl” refers herein to the group —C(O)—NRR′ whereR is loweralkyl and R′ is hydrogen or a loweralkyl. The term“arylaminocarbonyl” refers herein to the group —C(O)—NRR′ where R is anaryl and R′ is hydrogen, loweralkyl or aryl. “aralkylaminocarbonyl”refers herein to the group —C(O)—NRR′ where R is loweraralkyl and R′ ishydrogen, loweralkyl, aryl, or loweraralkyl.

[0076] “Aminosulfonyl” refers herein to the group —S(O)₂—NH₂.“Substituted aminosulfonyl” refers herein to the group —S(O)₂—NRR′ whereR is loweralkyl and R′ is hydrogen or a loweralkyl. The term“aralkylaminosulfonlyaryl” refers herein to thegroup-aryl-S(O)₂—NH-aralkyl, where the aralkyl is loweraralkyl.

[0077] “Carbonyl” refers to the divalent group —C(O)—.

[0078] “Carbonyloxy” refers generally to the group —C(O)—O. Such groupsinclude esters, —C(O)—O—R, where R is loweralkyl, cycloalkyl, aryl, orloweraralkyl. The term “carbonyloxycycloalkyl” refers generally hereinto both an “carbonyloxycarbocycloalkyl” and an“carbonyloxyheterocycloalkyl”, i.e., where R is a carbocycloalkyl orheterocycloalkyl, respectively. The term “arylcarbonyloxy” refers hereinto the group —C(O)—O-aryl, where aryl is a mono- or polycyclic,carbocycloaryl or heterocycloaryl. The term “aralkylcarbonyloxy” refersherein to the group —C(O)—O-aralkyl, where the aralkyl is loweraralkyl.

[0079] The term “sulfonyl” refers herein to the group —SO₂—.“Alkylsulfonyl” refers to a substituted sulfonyl of the structure —SO₂R—in which R is alkyl. Alkylsulfonyl groups employed in compounds of thepresent invention are typically loweralkylsulfonyl groups having from 1to 6 carbon atoms in its backbone structure. Thus, typical alkylsulfonylgroups employed in compounds of the present invention include, forexample, methylsulfonyl (i.e., where R is methyl), ethylsulfonyl (i.e.,where R is ethyl), propylsulfonyl (i.e., where R is propyl), and thelike. The term “arylsulfonyl” refers herein to the group —SO₂-aryl. Theterm “aralkylsulfonyl” refers herein to the group —SO₂-aralkyl, in whichthe aralkyl is loweraralkyl. The term “sulfonamido” refers herein to—SO₂NH₂.

[0080] As used herein, the term “carbonylamino” refers to the divalentgroup —NH—C(O)— in which the hydrogen atom of the amide nitrogen of thecarbonylamino group can be replaced a loweralkyl, aryl, or loweraralkylgroup. Such groups include moieties such as carbamate esters(—NH—C(O)—O—R) and amides —NH—C(O)—O—R, where R is a straight orbranched chain loweralkyl, cycloalkyl, or aryl or loweraralkyl. The term“loweralkylcarbonylamino” refers to alkylcarbonylamino where R is aloweralkyl having from 1 to about 6 carbon atoms in its backbonestructure. The term “arylcarbonylamino” refers to group —NH—C(O)—R whereR is an aryl. Similarly, the term “aralkylcarbonylamino ” refers tocarbonylamino where R is a lower aralkyl. As used herein, the term“aminocarbonyl” refers to the divalent group —C(O)—NH— in which thehydrogen atom of the amide nitrogen of the carbonylamino group can bereplaced a loweralkyl, aryl, or loweraralkyl group, as described above.

[0081] As used herein, the term “guanidino” or “guanidyl” refers tomoieties derived from guanidine, H₂N—C(═NH)—NH₂. Such moieties includethose bonded at the nitrogen atom carrying the formal double bond (the“2”-position of the guanidine, e.g., diaminomethyleneamino, (H₂N)₂C═NH—)and those bonded at either of the nitrogen atoms carrying a formalsingle bond (the “1-” and/or “3”-positions of the guandine, e.g.,H₂N—C(═NH)—NH—). The hydrogen atoms at any of the nitrogens can bereplaced with a suitable substituent, such as loweralkyl, aryl, orloweraralkyl.

[0082] As used herein, the term “amidino” refers to the moietiesR—C(═N)—NR′— (the radical being at the “N¹” nitrogen) and R(NR′)C═N—(the radical being at the “N²”, nitrogen), where R and R′ can behydrogen, loweralkyl, aryl, or loweraralkyl.

[0083] “Cycloalkyl” refers to a mono- or polycyclic, heterocyclic orcarbocyclic alkyl substituent. Typical cycloalkyl substituents have from3 to 8 backbone (i.e., ring) atoms in which each backbone atom is eithercarbon or a heteroatom. The term “heterocycloalkyl” refers herein tocycloalkyl substituents that have from 1 to 5, and more typically from 1to 4 heteroatoms in the ring structure. Suitable heteroatoms employed incompounds of the present invention are nitrogen, oxygen, and sulfur.Representative heterocycloalkyl moieties include, for example,morpholino, piperazinyl, piperadinyl and the like. Carbocycloalkylgroups are cycloalkyl groups in which all ring atoms are carbon. Whenused in connection with cycloalkyl substituents, the term “polycyclic”refers herein to fused and non-fused alkyl cyclic structures.

[0084] The term “substituted heterocycle” or “heterocyclic group” orheterocycle as used herein refers to any 3- or 4-membered ringcontaining a heteroatom selected from nitrogen, oxygen, and sulfur or a5- or 6-membered ring containing from one to three heteroatoms selectedfrom the group consisting of nitrogen, oxygen, or sulfur; wherein the5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3double bonds; wherein the nitrogen and sulfur atom maybe optionallyoxidized; wherein the nitrogen and sulfur heteroatoms maybe optionallyquarternized; and including any bicyclic group in which any of the aboveheterocyclic rings is fused to a benzene ring or another 5- or6-membered heterocyclic ring independently defined above. The term“heterocycle” thus includes rings in which nitrogen is the heteroatom aswell as partially and fully-saturated rings. Preferred heterocyclesinclude, for example: diazapinyl, pyrryl, pyrrolinyl, pyrrolidinyl,pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazoyl, imidazolinyl,imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, N-methylpiperazinyl, azetidinyl, N-methylazetidinyl, pyrimidinyl, pyridazinyl,oxazolyl, oxazolidinyl, isoxazolyl, isoazolidinyl, morpholinyl,thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl,quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,furyl, thienyl, triazolyl and benzothienyl.

[0085] Heterocyclic moieties can be unsubstituted or monosubstituted ordisubstituted with various substituents independently selected fromhydroxy, halo, oxo (C═O), alkylimino (RN═, wherein R is a loweralkyl orloweralkoxy group), amino, alkylamino, dialkylamino, acylaminoalkyl,alkoxy, thioalkoxy, polyalkoxy, loweralkyl, cycloalkyl or haloalkyl.

[0086] The heterocyclic groups may be attached at various positions aswill be apparent to those having skill in the organic and medicinalchemistry arts in conjunction with the disclosure herein.

[0087] where R is H or a heterocyclic substituent, as described herein.

[0088] Representative heterocyclics include, for example, imidazolyl,pyridyl, piperazinyl, azetidinyl, thiazolyl, furanyl, triazolylbenzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, phthalazinyl, indolyl, naphthpyridinyl,indazolyl, and quinolizinyl.

[0089] “Aryl” refers to optionally substituted monocyclic and polycyclicaromatic groups having from 3 to 14 backbone carbon or hetero atoms, andincludes both carbocyclic aryl groups and heterocyclic aryl groups.Carbocyclic aryl groups are aryl groups in which all ring atoms in thearomatic ring are carbon. The term “heteroaryl” refers herein to arylgroups having from 1 to 4 heteroatoms as ring atoms in an aromatic ringwith the remainder of the ring atoms being carbon atoms. When used inconnection with aryl substituents, the term “polycyclic aryl” refersherein to fused and non-fused cyclic structures in which at least onecyclic structure is aromatic, such as, for example, benzodioxozolo(which has a heterocyclic structure fused to a phenyl group, i.e.,

[0090] naphthyl, and the like. Exemplary aryl moieties employed assubstituents in compounds of the present invention include phenyl,pyridyl, pyrimidinyl, thiazolyl, indolyl, imidazolyl, oxadiazolyl,tetrazolyl, pyrazinyl, triazolyl, thiophenyl, furanyl, quinolinyl,purinyl, naphthyl, benzothiazolyl, benzopyridyl, and benzimidazolyl, andthe like.

[0091] “Aralkyl” refers to an alkyl group substituted with an arylgroup. Typically, aralkyl groups employed in compounds of the presentinvention have from 1 to 6 carbon atoms incorporated within the alkylportion of the aralkyl group. Suitable aralkyl groups employed incompounds of the present invention include, for example, benzyl,picolyl, and the like.

[0092] Representative heteroaryl groups include, for example, thoseshown below. These heteroaryl groups can be further substituted and maybe attached at various positions as will be apparent to those havingskill in the organic and medicinal chemistry arts in conjunction withthe disclosure herein.

[0093] Representative heteroaryl's include, for example, imidazolyl,pyridyl, piperazinyl, azetidinyl, thiazolyl, triazolyl benzimidazolyl,benzothiazolyl, and benzoxazolyl.

[0094] The term “biaryl” refers to a group or substituent to which twoaryl groups, which are not condensed to each other, are bound. Exemplarybiaryl compounds include, for example, phenylbenzene, diphenyldiazene,4-methylthio-1-phenylbenzene, phenoxybenzene, (2-phenylethynyl)benzene,diphenyl ketone, (4-phenylbuta-1,3-diynyl)benzene, phenylbenzylamine,(phenylmethoxy)benzene, and the like. Preferred optionally substitutedbiaryl groups include:2-(phenylamino)-N-[4-(2-phenylethynyl)-phenyl]acetamide,1,4-diphenylbenzene,N-[4-(2-phenylethynyl)phenyl]-2-[benzyl-amino]acetamide,2-amino-N-[4-(2-phenylethynyl)phenyl]propanamide,2-amino-N-[4-(2-phenylethynyl)phenyl]acetamide,2-(cyclopropylamino)-N-[4-(2-phenylethynyl)-phenyl]acetamide,2-(ethylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide,2-[(2-methylpropyl)amino]-N-[4-(2-phenylethynyl)phenyl]acetamide,5-phenyl-2H-benzo-[d]1,3-dioxolene, 2-chloro-1-methoxy-4-phenylbenzene,2-[(imidazolylmethyl)amino]-N-[4-(2-phenylethynyl)phenyl]acetamide,4-phenyl-1-phenoxybenzene,N-(2-aminoethyl)-[4-(2-phenylethynyl)phenyl]carboxamide,2-{[(4-fluorophenyl)methyl]amino}-N-[4-(2-phenylethynyl)phenyl]acetamide,2-{[(4-methylphenyl)methyl]amino}-N-[4-(2-phenyl-ethynyl)phenyl]acetamide,4-phenyl-1-(trifluoromethyl)benzene, 1-butyl-4-phenyl-benzene,2-(cyclohexylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide,2-(ethylmethyl-amino)-N-[4-(2-phenylethynyl)phenyl]acetamide,2-(butylamino)-N-[4-(2-phenyl-ethynyl)phenyl]acetamide,N-[4-(2-phenylethynyl)phenyl]-2-(4-pyridylamino)acetamide,N-[4-(2-phenylethynyl)phenyl]-2-(quinuclidin-3-ylamino)acetamide,N-[4-(2-phenyl-ethynyl)phenyl]pyrrolidin-2-ylcarboxamide,2-amino-3-methyl-N-[4-(2-phenylethynyl)-phenyl]butanamide,4-(4-phenylbuta-1,3-diynyl)phenylamine,2-(dimethylamino)-N-[4-(4-phenylbuta-1,3-diynyl)phenyl]acetamide,2-(ethylamino)-N-[4-(4-phenylbuta-1,3-diynyl)phenyl]acetamide,4-ethyl-1-phenylbenzene, 1-[4-(2-phenylethynyl)phenyl]ethan-1-one,N-(1-carbamoyl-2-hydroxypropyl)[4-(4-phenylbuta-1,3-diynyl)phenyl]carboxamide,N-[4-(2-phenylethynyl)phenyl]propanamide, 4-methoxyphenyl phenyl ketone,phenyl-N-benzamide, (tert-butoxy)-N-[(4-phenylphenyl)methyl]carboxamide,2-(3-phenylphenoxy)ethanehydroxamic acid, 3-phenylphenyl propanoate,1-(4-ethoxyphenyl)-4-methoxybenzene, and[4-(2-phenylethynyl)phenyl]pyrrole.

[0095] The term “heteroarylaryl” refers to a biaryl group where one ofthe aryl groups is a heteroaryl group. Exemplary heteroarylaryl groupsinclude, for example, 2-phenylpyridine, phenylpyrrole,3-(2-phenylethynyl)pyridine, phenylpyrazole,5-(2-phenylethynyl)-1,3-dihydropyrimidine-2,4-dione,4-phenyl-1,2,3-thiadiazole, 2-(2-phenylethynyl)pyrazine,2-phenylthiophene, phenylimidazole, 3-(2-piperazinylphenyl)-furan,3-(2,4-dichlorophenyl)-4-methylpyrrole, and the like. Preferredoptionally substituted heteroarylaryl groups include:5-(2-phenylethynyl)pyrimidine-2-ylamine, 1-methoxy-4-(2-thienyl)benzene,1-methoxy-3-(2-thienyl)benzene, 5-methyl-2-phenyl-pyridine,5-methyl-3-phenylisoxazole, 2-[3-(trifluoromethyl)phenyl]furan,3-fluoro-5-(2-furyl)-2-methoxy-1-prop-2-enylbenzene,(hydroxyimino)(5-phenyl(2-thienyl))-methane,5-[(4-methylpiperazinyl)methyl]-2-phenylthiophene,2-(4-ethylphenyl)thiophene, 4-methylthio-1-(2-thienyl)benzene,2-(3-nitrophenyl)thiophene,(tert-butoxy)-N-[(5-phenyl(3-pyridyl))methyl]carboxamide,hydroxy-N-[(5-phenyl(3-pyridyl))methyl]-amide,2-(phenylmethylthio)pyridine, and benzylimidazole.

[0096] The term “heteroarylheteroaryl” refers to a biaryl group whereboth of the aryl groups is a heteroaryl group. Exemplaryheteroarylheteroaryl groups include, for example, 3-pyridylimidazole,2-imidazolylpyrazine, and the like. Preferred optionally substitutedheteroarylheteroaryl groups include: 2-(4-piperazinyl-3-pyridyl)furan,diethyl-(3-pyrazin-2-yl(4-pyridyl))amine, anddimethyl{2-[2-(5-methylpyrazin-2-yl)ethynyl](4-pyridyl)}amine.

[0097] “Optionally substituted” or “substituted” refers to thereplacement of one or more hydrogen atoms with a monovalent or divalentradical. Suitable substitution groups include, for example, hydroxyl,nitro, amino, imino, cyano, halo, thio, sulfonyl, thioamido, amidino,imidino, oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido,carboxyl, formyl, loweralkyl, haloloweralkyl, loweralkyamino,haloloweralkylamino, loweralkoxy, haloloweralkoxy, loweralkoxyalkyl,alkylcarbonyl, aminocarbonyl, arylcarbonyl, aralkylcarbonyl,heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl,cyanoalkyl, aryl and the like.

[0098] The substitution group can itself be substituted. The groupsubstituted onto the substitution group can be carboxyl, halo; nitro,amino, cyano, hydroxyl, loweralkyl, loweralkoxy, aminocarbonyl, —SR,thioamido, —SO₃H, —SO₂R or cycloalkyl, where R is typically hydrogen,hydroxyl or loweralkyl.

[0099] When the substituted substituent includes a straight chain group,the substitution can occur either within the chain (e.g.,2-hydroxypropyl, 2-aminobutyl, and the like) or at the chain terminus(e.g., 2-hydroxyethyl, 3-cyanopropyl, and the like). Substitutedsubstitutents can be straight chain, branched or cyclic arrangements ofcovalently bonded carbon or heteroatoms.

[0100] As used herein, the term “carboxy-protecting group” refers to acarbonyl group which has been esterified with one of the commonly usedcarboxylic acid protecting ester groups employed to block or protect thecarboxylic acid function while reactions involving other functionalsites of the compound are carried out. In addition, a carboxy protectinggroup can be attached to a solid support whereby the compound remainsconnected to the solid support as the carboxylate until cleaved byhydrolytic methods to release the corresponding free acid.Representative carboxy-protecting groups include, for example,loweralkyl esters, secondary amides and the like.

[0101] As used herein, the term “pharmaceutically acceptable salts”refers to the nontoxic acid or alkaline earth metal salts of thecompounds of Formula I. These salts can be prepared in situ during thefinal isolation and purification of the compounds of Formula I, or byseparately reacting the base or acid functions with a suitable organicor inorganic acid or base, respectively. Representative salts includebut are not limited to the following: acetate, adipate, alginate,citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, cyclopentanepropionate,dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-napthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylproionate, picrate, pivalate, propionate,succinate, sulfate, tartrate, thiocyanate,. p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as loweralkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

[0102] Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, methanesulfonic acid, succinic acidand citric acid. Basic addition salts can be prepared in situ during thefinal isolation and purification of the compounds of formula (I), orseparately by reacting carboxylic acid moieties with a suitable basesuch as the hydroxide, carbonate or bicarbonate of a pharmaceuticallyacceptable metal cation or with ammonia, or an organic primary,secondary or tertiary amine. Pharmaceutically acceptable salts include,but are not limited to, cations based on the alkali and alkaline earthmetals, such as sodium, lithium, potassium, calcium, magnesium, aluminumsalts and the like, as well as nontoxic ammonium, quaternary ammonium,and amine cations, including, but not limited to ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, ethylamine, and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine and the like.

[0103] As used herein, the term “pharmaceutically acceptable ester”refers to esters, which hydrolyze in vivo and include those that breakdown readily in the human body to leave the parent compound or a saltthereof. Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include formates, acetates, propionates,butyrates, acrylates and ethylsuccinates.

[0104] The term “pharmaceutically acceptable prodrugs” as used hereinrefers to those prodrugs of the compounds of the present invention whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use,as well as the zwitterionic forms, where possible, of the compounds ofthe invention. The term “prodrug” refers to compounds that are rapidlytransformed in vivo to yield the parent compound of the above formula,for example by hydrolysis in blood. A thorough discussion is provided inT. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14of the A.C.S. Symposium Series, and in Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

[0105] The term “cancer” refers to cancer diseases that can bebeneficially treated by the inhibition of Raf kinase, including, forexample, solid cancers, such as carcinomas (e.g., of the lungs,pancreas, thyroid, bladder or colon), myeloid disorders (e.g., myeloidleukemia) and adenomas (e.g., villous colon adenoma).

[0106] In illustrative embodiments of the invention, A₁ may be, forexample, phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl,pyrimidinylalkyl, heterocyclocarbonylphenyl, heterocyclophenyl,heterocycloalkylphenyl, chlorophenyl, flourophenyl, bromophenyl,iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl, 4-chlorophenyl,alkylbenzoate, alkoxyphenyl, dialkoxyphenyl, dialkylphenyl,trialkylphenyl, thiophene, thiophene-2-carboxylate, alkylthiophenyl,trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl,cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl,alkylchlorophenyl, alkylflourophenyl, triflouromethylchlorophenyl,triflouromethylbromophenyl indenyl, 2,3-dihydroindenyl, tetralinyl,triflourophenyl, (triflouromethyl)thiophenyl, alkoxybiphenyl,morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl,cyclohexylalkyl, indolyl, 2,3-dihydroindolyl,1-aceyt-1,2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl,hydroxyphenyl, hydroxy-alkylphenyl, pyrrolidinyl, pyrrolidin-1-yl,pyrrolidin-1-ylalkyl, 4-amino(imino)-methylphenyl, isoxazolyl,indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl,benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl,benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl,phenylsulfonyl, phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl,piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl,pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl,N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl,hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl,1,4′-bipiperidin-1′-yl, or (1,4′-bipiperidin-1′-ylcarbonyl)phenyl, whichmay be substituted by one or more substitutents selected from the groupconsisting of hydroxyl, nitro, cyano, halo, and substituted orunsubstituted amino, imino, thio, sulfonyl, thioamido, amidino, imidino,oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido,carboxyl, formyl, loweralkyl, haloloweralkyl, loweralkyamino,haloloweralkylamino, loweralkoxy, haloloweralkoxy, loweralkoxyalkyl,alkylcarbonyl, aminocarbonyl, loweralkylaminocarbonyl,heterocycloalkylloweralkylaminocarbonyl,carboxylloweralkylaminocarbonyl, aryl-carbonyl, aralkylcarbonyl,heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl,cyanoalkyl, aryl and the like. In some particularly preferredembodiments, A₁ is substituted or unsubstituted phenyl. In otherillustrative embodiments of the invention, A₂ may be, for example,pyridyl, which may be substituted by one or more substitutents selectedfrom the group consisting of hydroxyl, nitro, cyano, halo, andsubstituted or unsubstituted amino, imino, thio, sulfonyl, thioamido,amidino, imidino, oxo, oxamidino, methoxamidino, imidino, guanidino,sulfonamido, carboxyl, formyl, loweralkyl, haloloweralkyl,loweralkyamino, haloloweralkylamino, loweralkoxy, haloloweralkoxy,loweralkoxyalkyl, alkylcarbonyl, aminocarbonyl, loweralkylaminocarbonyl,heterocycloalkylloweralkylaminocarbonyl,carboxylloweralkylaminocarbonyl, arylcarbonyl, aralkylcarbonyl,heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl,cyanoalkyl, aryl and the like.

[0107] In representative embodiments of the invention, the compounds ofthe invention include, for example,4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide,4-({2-[(3-chlorophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-({2-[(4-bromophenyl)-amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-({2-[(3-chloro-4-fluorophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,N-methyl-4-{[2-(phenylamino)-1H-benzimidazol-6-yl]oxy}pyridine-2-carboxamide,4-[(2-{[4-bromo-2-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide,N-methyl-4-({2-[(2-methylpropyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide,4-[(2-{[4-(dimethylamino)naphthalen-1-yl]-amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide,N-methyl-4-({2-[(4-nitrophenyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide,N-methyl-4-({2-[(phenylcarbonyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide,N-methyl-4-({2-[(phenylmethyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide,methyl4-{[6-({2-[(methylamino)carbonyl]pyridin-4-yl}oxy)-1H-benzimidazol-2-yl]amino}benzoate,4-({2-[(4-chlorophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-[(2-{[2-(ethyloxy)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide,N-methyl-4-({2-[(2-morpholin-4-ylethyl)-amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide,4-({2-[(4-iodophenyl)-amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,N-methyl-4-[(2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]pyridine-2-carboxamide,4-({2-[(furan-2-ylmethyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-({2-[(4-bromo-3-methylphenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-({2-[(4-acetylphenyl)amino]-1H-benzimidazol-6-yl}-oxy)-N-methylpyridine-2-carboxamide,N-methyl-4-({2-[(2,4,6-trimethylphenyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide,4-[(2-{[4-(1,1-dimethylethyl)-phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide,4-({2-[(2-bromophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-({2-[(3-bromophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-({2-[(2-chlorophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,methyl 3-{[6-({2-[(methylamino)carbonyl]pyridin-4-yl}oxy)-1H-benzimidazol-2-yl]amino}thiophene-2-carboxylate,4-({2-[(4-bromophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-{(3R,5R)-5-[(methyloxy)methyl]pyrrolidin-3-yl}pyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide,4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide,N-methyl-4-[(1-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-ethylpyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-hydroxyethyl)pyridine-2-carboxamide,4-({2-[(4-bromo-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N,N-dimethylpyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide,N-(4-bromophenyl)-1-methyl-5-{[2-(pyrrolidin-1-ylcarbonyl)pyridin-4-yl]oxy}-1H-benzimidazol-2-amine,ethyl(3R)-3-(methyloxy)-4-[({4-[(2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-carbonyl)amino]piperidine-1-carboxylate,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(dimethylamino)ethyl]pyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(tetrahydrofuran-2-yl-methyl)pyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-morpholin-4-ylethyl)pyridine-2-carboxamide,4-({2-[(4-bromo-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(piperidin-4-ylmethyl)pyridine-2-carboxamide,5-({2-[(3-aminopyrrolidin-1-yl)carbonyl]pyridin-4-yl}oxy)-N-(4-bromophenyl)-1-methyl-1H-benzimidazol-2-amine,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[1-(diphenylmethyl)azetidin-3-yl]pyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-piperidin-3-ylpyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(1,3-thiazol-2-yl)pyridine-2-carboxamide,and4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[(1-ethylpyrrolidin-2-yl)-methyl]pyridine-2-carboxamide,(4-{2-[(4-bromophenyl)amino]benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide,(4-{2-[(4-bromophenyl)amino]benzoxazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide,and other representative compounds set forth in the Examples.

[0108] In other aspects, the present invention relates to the processesfor preparing the compounds of Formulas I, II, III, IV and V and to thesynthetic intermediates useful in such processes.

[0109] The compounds of the invention comprise asymmetricallysubstituted carbon atoms. Such asymmetrically substituted carbon atomscan result in the compounds of the invention comprising mixtures ofstereoisomers at a particular asymmetrically substituted carbon atom ora single stereoisomer. As a result, racemic mixtures, mixtures ofdiastereomers, as well as single diastereomers of the compounds of theinvention are included in the present invention. The terms “S” and “R”configuration, as used herein, are as defined by the IUPAC 1974RECOMMENDATIONS FOR SECTION E, FUNDAMENTAL STEREOCHEMISTRY, Pure Appl.Chem. 45:13-30 (1976). The terms α and β are employed for ring positionsof cyclic compounds. The α-side of the reference plane is that side onwhich the preferred substituent lies at the lower numbered position.Those substituents lying on the opposite side of the reference plane areassigned β descriptor. It should be noted that this usage differs fromthat for cyclic stereoparents, in which “α” means “below the plane” anddenotes absolute configuration. The terms α and β configuration, as usedherein, are as defined by the CHEMICAL ABSTRACTS INDEX GUIDE-APPENDIX IV(1987) paragraph 203.

[0110] The present invention also relates to the processes for preparingthe compounds of the invention and to the synthetic intermediates usefulin such processes, as described in detail, below.

[0111] Synthetic Methods

[0112] Compounds of the invention containing a benzimidazole core may beprepared using a number of methods familiar to one of skill in the art.In one method, suitably functionalized diamines may be coupled withvarious thioisocyanates to form the intermediate thioureas. Cyclizationto form the benzimidazole moiety may be effected under known conditionssuch as with treatment carbodiimides or alkyl halides as in thefollowing schemes.

[0113] Alternatively the diamines may be reacted sequentially withcarbonyl diimidazole and phosphoryl chloride followed by coupling withthe appropriate amine.

[0114] Compounds containing the oxazole structure may similarly beprepared according to the methods above or according to other knowngeneral procedures. Haviv et al. (J. Med. Chem. 1988, 31:1719) describesa procedure for assembling oxazole cores wherein a hydroxy aniline istreated with ethyl potassium xanthate. The resulting sulfurylbenzoxazole may then be chlorinated and coupled with an amine.

[0115] Compounds containing a benzothiazole core may also be preparedaccording to known methods. An ortho-halothioisocyanate may be reactedwith an amine to form a thiourea. Reduction with NaH then allowsformation of the thiazole ring.

[0116] Benzothiazoles may generally be substituted in accordance withthe present invention, such as through the following synthetic pathway:

[0117] Benzoxzoles may generally be synthesized through the followingpathway:

[0118] The compounds of the invention are useful in vitro or in vivo ininhibiting the growth of cancer cells. The compounds may be used aloneor in compositions together with a pharmaceutically acceptable carrieror excipient. Suitable pharmaceutically acceptable carriers orexcipients include, for example, processing agents and drug deliverymodifiers and enhancers, such as, for example, calcium phosphate,magnesium stearate, talc, monosaccharides, disaccharides, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,dextrose, hydroxypropyl-β-cyclodextrin, polyvinyl-pyrrolidinone, lowmelting waxes, ion exchange resins, and the like, as well ascombinations of any two or more thereof. Other suitable pharmaceuticallyacceptable excipients are described in “Remington's PharmaceuticalSciences,” Mack Pub. Co., New Jersey (1991), incorporated herein byreference.

[0119] Effective amounts of the compounds of the invention generallyinclude any amount sufficient to detectably inhibit Raf activity by anyof the assays described herein, by other Raf kinase activity assaysknown to those having ordinary skill in the art or by detecting aninhibition or alleviation of symptoms of cancer.

[0120] The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. It willbe understood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination, and the severity of the particular diseaseundergoing therapy. The therapeutically effective amount for a givensituation can be readily determined by routine experimentation and iswithin the skill and judgment of the ordinary clinician.

[0121] For purposes of the present invention, a therapeuticallyeffective dose will generally be a total daily dose administered to ahost in single or divided doses may be in amounts, for example, of from0.001 to 1000 mg/kg body weight daily and more preferred from 1.0 to 30mg/kg body weight daily. Dosage unit compositions may contain suchamounts of submultiples thereof to make up the daily dose.

[0122] The compounds of the present invention may be administeredorally, parenterally, sublingually, by aerosolization or inhalationspray, rectally, or topically in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvants,and vehicles as desired. Topical administration may also involve the useof transdermal administration such as transdermal patches orionophoresis devices. The term parenteral as used herein includessubcutaneous injections, intravenous, intramuscular, intrasternalinjection, or infusion techniques.

[0123] Injectable preparations, for example, sterile injectable aqueousor oleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-propanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordi-glycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

[0124] Suppositories for rectal administration of the drug can beprepared by mixing the drug with a suitable nonirritating excipient suchas cocoa butter and polyethylene glycols, which are solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum and release the drug.

[0125] Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

[0126] Liquid dosage forms for oral administration may includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art, such aswater. Such compositions may also comprise adjuvants, such as wettingagents, emulsifying and suspending agents, cyclodextrins, andsweetening, flavoring, and perfuming agents.

[0127] The compounds of the present invention can also be administeredin the form of liposomes. As is known in the art, liposomes aregenerally derived from phospholipids or other lipid substances.Liposomes are formed by mono- or multi-lamellar hydrated liquid crystalsthat are dispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and metabolizable lipid capable of forming liposomes can beused. The present compositions in liposome form can contain, in additionto a compound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natural and synthetic. Methodsto form liposomes are known in the art. See, for example, Prescott, Ed.,Methods in Cell Biology, Volume XIV, Academic Press, New York, N.W., p.33 et seq. (1976).

[0128] While the compounds of the invention can be administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more other agents used in the treatment of cancer.Representative agents useful in combination with the compounds of theinvention for the treatment of cancer include, for example, irinotecan,topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin,cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids,imatinib (Gleevec), anthracyclines, rituximab, trastuzumab, as well asother cancer chemotherapeutic agents.

[0129] The above compounds to be employed in combination with thecompounds of the invention will be used in therapeutic amounts asindicated in the Physicians' Desk Reference (PDR) 47th Edition (1993),which is incorporated herein by reference, or such therapeuticallyuseful amounts as would be known to one of ordinary skill in the art.

[0130] The compounds of the invention and the other anticancer agentscan be administered at the recommended maximum clinical dosage or atlower doses. Dosage levels of the active compounds in the compositionsof the invention may be varied so as to obtain a desired therapeuticresponse depending on the route of administration, severity of thedisease and the response of the patient. The combination can beadministered as separate compositions or as a single dosage formcontaining both agents. When administered as a combination, thetherapeutic agents can be formulated as separate compositions, which aregiven at the same time or different times, or the therapeutic agents,can be given as a single composition.

[0131] Antiestrogens, such as tamoxifen, inhibit breast cancer growththrough induction of cell cycle arrest, that requires the action of thecell cycle inhibitor p27Kip. Recently, it has been shown that activationof the Ras-Raf-MAP Kinase pathway alters the phosphorylation status ofp27Kip such that its inhibitory activity in arresting the cell cycle isattenuated, thereby contributing to antiestrogen resistance (Donovan etal, J. Biol. Chem. 276:40888, 2001). As reported by Donovan et al.,inhibition of MAPK signaling through treatment with MEK inhibitorchanged the phosphorylation status of p27 in hormone refactory breastcancer cell lines and in so doing restored hormone sensitivity.Accordingly, in one aspect, the compounds of formulas (I), (II), (III),(IV) and (V) may be used in the treatment of hormone dependent cancers,such as breast and prostate cancers, to reverse hormone resistancecommonly seen in these cancers with conventional anticancer agents.

[0132] In hematological cancers, such as chronic myelogenous leukemia(CML), chromosomal translocation is responsible for the constitutivelyactivated BCR-AB1 tyrosine kinase. The afflicted patients are responsiveto Gleevec, a small molecule tyrosine kinase inhibitor, as a result ofinhibition of Ab1 kinase activity. However, many patients with advancedstage disease respond to Gleevec initially, but then relapse later dueto resistance-conferring mutations in the Ab1 kinase domain. In vitrostudies have demonstrated that BCR-Av1 employs the Raf kinase pathway toelicit its effects. In addition, inhibiting more than one kinase in thesame pathway provides additional protection againstresistance-conferring mutations. Accordingly, in another aspect of theinvention, the compounds of formulas (I), (II), (III), (IV) and (V) areused in combination with at least one additional agent, such as Gleevec,in the treatment of hematological cancers, such as chronic myelogenousleukemia (CML), to reverse or prevent resistance to the at least oneadditional agent.

[0133] The present invention will be understood more readily byreference to the following examples, which are provided by way ofillustration and are not intended to be limiting of the presentinvention.

[0134] Representative side chains for use in the compounds of thefollowing examples may generally be prepared in accordance with thefollowing procedures:

EXAMPLE 1 Synthesis of4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide

[0135] The compound4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamidewas synthesized as follows:

[0136] Step 1. Synthesis of4-[(4-amino-3-nitrophenyl)oxy]-N-methylpyridine-2-carboxamide:

[0137] A mixture containing 4-amino-3-nitrophenol (1 eq) and potassiumbis(trimethylsilyl)amide (2 eq) was stirred in dimethylformamide for 2hours at room temperature. To this mixture was added(4-chloro(2-pyridyl))-N-methylcarboxamide (1 eq) and potassium carbonate(1.2 eq) and stirred at 90° C. for 3 days. The reaction mixture was thenconcentrated and partitioned between ethyl acetate and water. Theorganic layer was separated and washed with brine, dried, filtered, andconcentrated in vacuum to give brown solid. Purification on silica gel(2% triethyl amine/50% ethyl acetate in hexane) gave4-[(4-amino-3-nitrophenyl)oxy]-N-methylpyridine-2-carbox-amide as anorange solid. The product gave satisfactory NMR. HPLC, 3.39 min; MS:MH+=289.

[0138] Step 2. Synthesis of4-[(3,4-diaminophenyl)oxy]-N-methylpyridine-2-carboxamide:

[0139] The mixture containing [4-(3-amino-4-nitrophenoxy)(2-pyridyl)]-N—in methanol with catalytic amount of 10% Pd/C was hydrogenated untildisappearance of the yellow color to yield the product amine. HPLC, 2.5mins; MS: MH+=259.

[0140] Step 3. Synthesis of4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide:

[0141] The mixture containing4-[(3,4-diaminophenyl)oxy]-N-methylpyridine-2-carboxamide (1 eq) and4-chloro-3-(trifluoromethyl)benzeneisothiocyanate (1 eq) intetrahydrofuran was stirred at room temperature for 16 hours to give thecorresponding thiourea. To the resulting mixture was added1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (2 eq) andthe mixture was stirred for another 10 hours. The mixture wasconcentrated and partitioned between ethyl acetate and water. Theorganic layer was washed with brine and dried. Purification on HPLC gave4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methyl-pyridine-2-carboxamide.MS: MH+=462

EXAMPLES 2-108

[0142] The compounds shown in the following Table 1 (Examples 2-108)were prepared from following the procedure described for Example 1.TABLE 1 Example Structure Name MH+ 2

4-({2-[(3-chlorophenyl)amino]-1H- benzimidazol-6-yl}oxy)-N-methyl-pyridine-2-carboxamide 394 3

4-({2-[(4-bromophenyl)amino]- 1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide 440 4

4-({2-[(3-chloro-4-fluorophenyl)- amino]-1H-benzimidazol-6-yl}-oxy)-N-methylpyridine-2-carbox- amide 412 5

N-methyl-4-{[2-(phenylamino)- 1H-benzimidazol-6-yl]oxy}-pyridine-2-carboxamide 360 6

4-[(2-{[4-bromo-2-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methyl- pyridine-2-carboxamide 508 7

N-methyl-4-({2-[(2-methylpropyl)- amino]-1H-benzimidazol-6-yl}-oxy)pyridine-2-carboxamide 340 8

4-[(2-{[4-(dimethylamino)- naphthalen-1-yl]amino}-1H-benzimidazol-6-yl)oxy]-N-methyl- pyridine-2-carboxamide 453 9

N-methyl-4-({2-[(4-nitropropyl)- amino]-1H-benzimidazol-6-yl}-oxy)pyridine-2-carboxamide 405 10

N-methyl-4-({2-[(phenylcarbonyl)- amino]-1H-benzimidazol-6-yl}-oxy)pyridine-2-carboxamide 388 11

N-methyl-4-({2-[(phenylmethyl)- amino]-1H-benzimidazol-6-yl}-oxy)pyridine-2-carboxamide 374 12

methyl 4-{[6-({2-[(methylamino)- carbonyl]pyridin-4-yl}oxy)-1H-benzimidazol-2-yl]amino}benzoate 418 13

4-({2-[(4-chlorophenyl)amino]-1H- benzimidazol-6-yl}oxy)-N-methyl-pyridine-2-carboxamide 394 14

4-[(2-{[2-(ethyloxy)phenyl]- amino}-1H-benzimidazol-6-yl)-oxy]-N-methylpyridine-2- carboxamide 404 15

N-methyl-4-({2-[(2-morpholin-4- ylethyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide 397 16

4-({2-[(4-iodophenyl)amino]-1H- benzimidazol-6-yl}oxy)-N-methyl-pyridine-2-carboxamide 486 17

N-methyl-4-[(2-{[4-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]pyridine-2- carboxamide 428 18

4-({2-[(furan-2-ylmethyl)amino]- 1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide 364 19

4-({2-[(4-bromo-3-methylphenyl)- amino]-1H-benzimidazol-6-yl}-oxy)-N-methylpyridine-2- carboxamide 453 20

4-({2-[(4-acetylphenyl)amino]-1H- benzimidazol-6-yl}oxy)-N-methyl-pyridine-2-carboxamide 402 21

N-methyl-4-({2-[(2,4,6-trimethyl- phenyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide 402 22

4-[(2-{[4-(1,1-dimethylethyl)- phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2- carboxamide 416 23

4-({2-[(2-bromophenyl)amino]- 1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide 440 24

4-({2-[(3-bromophenyl)amino]- 1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide 440 25

4-({2-[(2-chlorophenyl)amino]-1H- benzimidazol-6-yl}oxy)-N-methyl-pyridine-2-carboxamide 394 26

methyl 3-{[6-({2-[(methylamino)- carbonyl]pyridin-4-yl}oxy)-1H-benzimidazol-2-yl]amino}- thiophene-2-carboxylate 424 27

4-({2-[(4-bromophenyl)amino]- 1H-benzimidazol-6-yl}oxy)-N-{(3R,5R)-5-[(methyloxy)methYl]- pyrrolidin-3-yl}pyridine-2- carboxamide539 28

(4-{2-[(2,4-difluorophenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 395.3 29

(4-{2-[(2,5-difluorophenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 395.3 30

N-methyl[4-(2-{[2-(trifluoro- methyl)phenyl]amino}-benzimidazol-5-yloxy)(2-pyridyl)]- carboxamide 427.3 31

(4-{2-[(3,4-dichlorophenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 428.2 32

N-methyl(4-{2-[(2-methylthio- phenyl)amino]benzimidazol-5-yloxy}(2-pyridyl))carboxamide 405.4 33

N-methyl(4-{2-[(4-methylthio- phenyl)amino]benzimidazol-5-yloxy}(2-pyridyl))carboxamide 405.4 34

(4-{2-[(2-methoxyphenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 389.4 35

(4-{2-[(2-fluorophenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 377.3 36

N-methyl(4-{2-[(4-sulfamoyl- phenyl)amino]benzimidazol-5-yloxy}(2-pyridyl))carboxamide 438.4 37

N-methyl[4-(2-{[2-(trifluoro- methoxy)phenyl]amino}-benzimidazol-5-yloxy)(2-pyridyl)]- carboxamide 443.3 38

(4-{2-[(3,4-dimethoxyphenyl)- amino]benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 419.4 39

[4-(2-{[2-fluoro-5-(trifluoro- methyl)phenyl]amino}-benzimidazol-5-yloxy)(2-pydidyl)]- N-methylcarboxamide 445.3 40

(4-{2-[(2,4-dichlorophenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 428.2 41

N-methyl[4-(2-{[3-(trifluoro- methyl)phenyl]amino}-benzimidazol-5-yloxy)(2-pyridyl)]- carboxamide 427.3 42

(4-{2-[(3-methoxyphenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 389.4 43

N-methyl(4-{2-[(2-phenylphenyl)- amino]benzimidazol-5-yloxy}(2-pyridyl))carboxamide 435.4 44

[4-(2-{[2-chloro-5-(trifluoro- methyl)phenyl]amino}-benzimidazol-5-yloxy)(2-pydidyl)]- N-methylcarboxamide 461.8 45

(4-{2-[(2,5-dimethoxyphenyl)- amino]benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 419.4 46

(4-{2-[(3,5-difluorophenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 395.3 47

(4-{2-[(2-ethylphenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 387.4 48

(4-{2-[(3,5-difluorophenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 395.4 49

[4-(2-{[3,5-bis(trifluoromethyl)- phenyl]amino}benzimidazol-5-yloxy)(2-pyridyl)]-N-methyl- carboxamide 495.4 50

(4-{2-[(2-methoxy-5- methylphenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 403.4 51

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-6-yloxy}(2-pyridyl))-N-methylcarboxamide 452.3 52

N-methyl[4-(2-{[2-(methylethyl)- phenyl]amino}benzimidazol-5-yloxy)(2-pyridyl)]carboxamide 401.4 53

(4-{2-[(2-methoxy-4-nitrophenyl)- amino]benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 434.4 54

(4-{2-[(3,5-dimethoxyphenyl)- amino]benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 420.1 55

(4-{2-[(5-chloro-2,4-dimethoxy- phenyl)amino]benzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 454.1 56

N-methyl-4-[(2-{[2-(1-methyl- ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2- carboxamide 402.5 57

N-methyl-4-[(2-{[2-(2-(methoxy)-4- nitrophenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2- carboxamide 435.4 58

4-({2-[(4-ethylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-methyl-pyridine-2- carboxamide 388.4 59

4-[(2-{[3,5-bis(methyloxy)phenyl]- amino}-1H-benzimidazol-5-yl)-oxy]-N-methylpyridine-2- carboxamide 420.4 60

4-[(2-{[5-chloro-2,4-bis(methyl- oxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 454.9 61

4-({2-[(4-cyclohexylphenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 442.5 62

4-({2-[(3,4-difluorophenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 396.4 63

4-({2-[(3,4-dimethylphenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 388.4 64

4-({2-[(4-bromo-3-chlorophenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 473.7 65

4-({2-[(4-butylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 416.5 66

N-methyl-4-[(2-{[4-(1-methyl- ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2- carboxamide 402.5 67

4-({2-[(2,6-dichlorophenyl)amino]- 1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 429.3 68

N-methyl-4-[(2-{[4-(phenyloxy)- phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide 452.5 69

4-({2-[(3,5-dimethylphenyl)- amino]-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 388.4 70

4-[(2-{[4-(diethylamino)phenyl]- amino}-1H-benzimidazol-5-yl)-oxy]-N-methylpyridine-2- carboxamide 431.5 71

4-({2-[(4-chloro-2-methylphenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 408.9 72

4-({2-[(4-bromo-2-chlorophenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 473.7 73

4-[(2-{[2-bromo-4-(1-methyl- ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 481.4 74

4-({2-[(2-chloro-4-methylphenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 408.9 75

4-({2-[(2-bromo-4-methylphenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 453.3 76

4-[(2-{[2-chloro-4-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 462.8 77

4-({2-[(4-chloro-2-fluorophenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 412.8 78

4-{[2-(2,3-dihydro-1H-inden-5- ylamino)-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 400.5 79

4-({2-[(2,5-dimethylphenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 388.4 80

4-({2-[(4-fluoro-2-methylphenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 392.4 81

N-methyl-4-({2-[(2,3,5-trifluoro- phenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide 414.4 82

4-({2-[(2-chloro-5-fluorophenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 412.8 83

4-({2-[(4-bromo-3-fluorophenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 457.3 84

4-[(2-{[3-(1,1-dimethylethyl)- phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2- carboxamide 416.5 85

4-({2-[(2,4-dibromophenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 518.2 86

4-({2-[(3-chloro-4-fluorophenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 412.8 87

4-[(2-{[4-bromo-2-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 507.3 88

4-({2-[(2,5-dichlorophenyl)amino]- 1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 429.3 89

N-methyl-4-{[2-({4-[(trifluoro- methyl)oxy]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2- carboxamide 444.4 90

4-{[2-(1,3-benzodioxol-5-yl- amino)-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 404.4 91

4-({2-[(3-chloro-4-methylphenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 408.9 92

4-({2-[(4-chloro-3-methylphenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 408.9 93

4-[(2-{[3-chloro-4-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 462.8 94

4-[(2-{[4-fluoro-3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 446.4 95

4-({2-[(4-chloro-3-fluorophenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 412.8 96

4-{[2-({4-bromo-2-[(trifluoro- methyl)oxy]phenyl}amino)-1H-benzimidazol-5-yl]oxy}-N-methyl- pyridine-2-carboxamide 523.3 97

N-methyl-4-[(2-{[3-(methylthio)- phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide 406.5 98

N-methyl-4-[(2-{[4-(methyloxy)- phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide 390.4 99

4-({2-[(3-ethylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 388.4 100

N-methyl-4-{[2-({4-[(trifluoro- methyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2- carboxamide 460.4 101

4-({2-[(4-fluorophenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 378.4 102

N-methyl-4-{[2-({3-[(trifluoro- methyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2- carboxamide 460.4 103

N-methyl-4-[(2-{[4-methyl-3- (trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 442.4 104

4-({2-[(4-bromo-2-fluorophenyl)- amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 457.3 105

4-[(2-{[5-chloro-2-(methyloxy)- phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2- carboxamide 424.9 106

N-methyl-4-[(2-{[4-(methyloxy)- 1,1′-biphenyl-3-yl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2- carboxamide 466.5 107

4-({2-[(3-fluorophenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 378.4 108

4-{[2-({3-bromo-4-[(trifluoro- methyl)oxy]phenyl}amino)-1H-benzimidazol-5-yl]oxy}-N-methyl- pyridine-2-carboxamide 523.3

EXAMPLE 109 Synthesis of(4-{2-[(4-bromophenyl)amino]-benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide

[0143] Step 1. Synthesis of 2-bromo-5-methoxybenzothiazole

[0144] A solution of bromine (3.6 eq) in chloroform (0.75M) was addeddropwise over a period of 1 hr to a stirred suspension of5-methoxy-2-mercaptobenzothiazole (1 eq) in chloroform at 0° C. Themixture was stirred for 30 min before it was added slowly to water andstirred for further 20 min. The mixture was filtered to remove a creamsolid. The organic phase was dried and evaporated to leave a brownsolid. The brown solid was dissolved in ether and filtered. The residuewas washed with ether and the filtrate and washings were combined andevaporated, chromatographed (4:1 hexanes and ethyl acetate) to give thetitle compound as a pale yellow solid. MS: MH⁺=244

[0145] Step 2. Synthesis of(4-bromophenyl)(5-methoxybenzothiazol-2-yl)amine

[0146] The mixture containing 2-bromo-5-methoxybenzthiazole (1 eq),4-Bromoaniline (2 eq) and diisopropylethylamine was subjected tomicrowave in NMP at 220° C. The resultant mixture was concentrated andpartitioned between ethyl acetate and water. The organic layer waswashed with brine and dried. Purification on silica gel gave the desiredproduct. MS: MH⁺=335

[0147] Step 3. Synthesis of 2-[(4-bromophenyl)amino]benzothiazol-5-ol

[0148] The mixture of (4-bromophenyl)(5-methoxybenzothiazol-2-yl)amineand hydrobromic acid (48%) was subjected to the microwave at 150° C. for6 mins to yield the desired product. MS: MH⁺=321

[0149] Step 4. Synthesis of(4-{2-[(4-bromophenyl)amino]benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide:

[0150] The mixture containing 2-[(4-bromophenyl)amino]benzothiazol-5-ol(1 eq), Potassiumbis(trimethylsilyl)amide (4 eq), was stirred indimethylformamide for 30 min at room temperature. To this mixture wasadded (4-chloro(2-pyridyl)-N-methyl-carboxamide (1 eq) and Potassiumcarbonate (1.2 eq) and microwaved for 6 mins at 150° C. The reactionmixture was then concentrated and partitioned between ethyl acetate andwater. The organic layer was separated and washed with brine, dried,filtered and concentrated. Purification on Prep LC yielded the desiredproduct. MS: MH⁺=455

[0151] Each of the Examples 110-119 shown in the following Table 2 weresynthesized according to the procedure described in Example 109: TABLE 2Ex- am- ple Structure Name MH+ 110

(4-{2-[(4-bromophenyl)amino]- benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 455 111

(4-{2-[(4-chlorophenyl)amino]- benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 411.1 112

N-methyl(4-{2-[(4-methylphenyl)- amino]benzothiazol-5-yloxy}(2-pyridyl))carboxamide 391.1 113

N-methyl[4-(2-{[4-(trifluoro- methoxy)phenyl]amino}-benzotiazol-5-yloxy)(2-pyridyl)]- carboxamide 461.1 114

(4-{2-[(4-butylphenyl)amino]- benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 433.2 115

N-methyl[4-(2-{[4-(methylethyl)- phenyl]amino}benzothiazol-5-yloxy)(2-pyridyl)]carboxamide 419.2 116

(4-{2-[(3,4-dichlorophenyl)amino]- benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 445 117

(4-{2-[(4-bromophenyl)amino]- benzothiazol-5-yloxy}(2-pyridyl))-N-(2-morpholin-4-ylethyl)- carboxamide 554.1 118

N-((3R)pyrrolidin-3-yl)(4-{2-[(4- bromophenyl)amino]benzothiazol-5-yloxy}(2-pyridyl))carboxamide 510 119

N-[(3R,5R)-5-(methoxymethyl)- pyrrolidin-3-yl](4-{2-[(4-bromo-phenyl)amino]benzothiazole 554.1

EXAMPLE 120a Synthesis of4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide

[0152] The compound4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamidewas synthesized as follows:

[0153] Step 1. Synthesis of4-{[3-amino-4-(methylamino)phenyl]oxy}-N-methyl-pyridine-2-carboxamide:

[0154] A solution of4-[(4-amino-3-nitrophenyl)oxy]-N-methylpyridine-2-carboxamide (1 eq) inmethylene chloride was treated with trifluoroacetic anhydride (1 eq) andstirred for 10 minutes at 0° C. The mixture was quenched with saturatedNaHCO3 solution. The organic layer was separated and washed with water,brine, dried and evaporated. MS: MH+=385.2.

[0155] To a solution of the trifluoroacetamide (1 eq) in a mixture oftoluene, acetonitrile and sodium hydroxide solution (50%) was addedbenzyltrimethylammonium chloride (1 eq) and dimethyl sulfate (1.2 eq).The biphasic mixture was stirred overnight at room temperature andevaporated. The mixture was taken up in ethyl acetate, washed withwater, brine, dried and evaporated. The crude product was purified bycolumn chromatography eluting with 1: 1 hexanes and ethyl acetatefollowed by 2% triethylamine in 1:1 hexanes and ethyl acetate followedby 2% triethylamine in 1:1 hexanes and ethyl acetate to affordN-methyl-4-{[4-(methylamino)-3-nitrophenyl]oxy}pyridine-2-carboxamide asa reddish orange solid. MS: MH+=303.1.

[0156] The solution of nitromethylaniline in methanol was treated with5% palladium on carbon and stirred under hydrogen atmosphere for 15 min.(until the disappearance of yellow coloration) at room temperature. Themixture was filtered and the filtrate was concentrated to provide 0.36 gof the diamine4-{[3-amino-4-(methylamino)phenyl]oxy}-N-methylpyridine-2-carboxamide.MS: MH+=273.3.

[0157] Step 2. Synthesis of4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide:

[0158] A solution of the diamine4-{[3-amino-4-(methylamino)phenyl]oxy}-N-methylpyridine-2-carboxamide (1eq) in methanol was treated with 4-bromophenyl-isothiocyanate (1 eq) andstirred at 60° C.-65° C. for 2 hours. The reaction mixture was cooleddown to room temperature and methyl iodide (1 eq) was added and stirredovernight at 60° C. The reaction was cooled to room temperature,evaporated, taken up in ethyl acetate, and washed with water and brine,dried, and evaporated under reduced pressure. Column chromatographyusing a gradient solvent system of hexanes and ethyl acetate and either1:1 methylene chloride and acetone or 5% methanol in methylene chlorideyielded the product as a half white powder. MS: MH+=452.3

EXAMPLE 120b Alternative Synthesis of4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide

[0159] Step 1. Synthesis ofN-methyl{4-[4-(methylamino)-3-aminophenoxy](2-pyridyl)}carboxamide:

[0160] A mixture containing 4-amino-3-nitrophenol 5 (1.0 g, 6.4 mmol),potassium bis(trimethylsilyl)amide (2.58 g, 12.8 mmol) was stirred inDMF (50 ml) for 2 hours at rt. To this mixture was added(4-chloro(2-pyridyl))-N-methylcarboxamide 4 (1.09 g, 6.4 mmol) andpotassium carbonate (0.5 g, 7.6 mmol) and stirred at 90° C. overnight.The reaction mixture was then concentrated and partitioned between ethylacetate and water. The organic layer was separated and washed with brine(2×10 ml), dried, filtered and concentrated in vacuum to give brownsolid. Purification on silica gel with 2% triethyl amine in 50% ethylacetate in hexane gave 1.3 g (yield, 72%) of[4-(4-amino-3-nitrophenoxy)(2-pyridyl)]-N-methylcarboxamide 6 as anorange solid: ¹H NMR (300 MHz, CDCl₃) δ 8.40 (d, J=5.6 Hz, 1 H), 7.99(br s, 1 H), 7.90 (d, J=2.7 Hz, 1H), 7.64 (d, J=2.7 Hz, 1 H), 7.17 (dd,J=2.7, 9.0 Hz, 1 H), 6.95 (ddd, J=0.7, 2.5, 5.6 Hz, 1 H), 6.89 (d, J=9.0Hz, 1 H), 6.18 (br s, 2 H), 3.00 (d, J=5.1 Hz, 3 H); mp 208-210° C. dec;LCMS m/z 289.2 (MH⁺), t_(R)=1.92 min.

[0161] A 500 mL three neck round bottom flask fitted with a mechanicalstirrer was charged with nitroaniline 6 (10.0 g, 34.8 mmol) and CH₂Cl₂(175 ml). The resulting suspension was cooled to 0° C. and TFAA (9.5 mL,14.1 g, 67.0 mmol) was added over 16 h while allowing the cooling bathto expire. After the reaction was judged complete by TLC,³ TBACl (5.2 g,17.5 mmol) and dimethyl sulfate (6.7 mL, 8.9 g, 70.0 mmol) were addedfollowed by 50% aqueous NaOH solution (140 mL). The resulting reactionmixture was cooled with an ice bath, and stirred vigorously for 1.5 h atrt. The reaction was then poured over ice water and the resulting phaseswere partitioned and separated. The aqueous phase was extracted withCH₂Cl₂ (3×100 mL) and the combined organic layers were washed with brine(2×100 mL), dried (MgSO₄), and concentrated. The crude residue waspurified by recrystallization (1:3 ethanol-water) to give 8.36 g (27.7mmol, 79%) of 7 as fine red needles: ¹H NMR (300 MHz, CDCl₃) δ 8.40 (dd,J=0.5, 4.9 Hz, 1 H), 8.07 (br d, J=3.7 Hz, 1 H), 7.98 (br s, 1 H), 7.95(d, J=2.9 Hz, 1 H), 7.62 (dd, J=0.5, 2.9 Hz, 1 H), 7.27 (ddd, J=0.5,2.9, 9.3 Hz, 1 H), 6.98 (dd, J=2.7, 5.6 Hz, 1 H), 6.92 (d, J=9.3 Hz, 1H), 3.07 (d, J=5.1 MHz, 3 H), 3.00 (d, J=5.1 Hz, 3 H); ¹³C NMR (75 MHz,CDCl₃) δ 166.6, 164.6, 152.6, 150.0, 144.8, 142.2, 130.6, 118.9, 115.5,114.2, 109.7, 30.2, 26.4; mp 164-166° C. LCMS m/z 303.4 (MH⁺),t_(R)=2.37 min.

[0162] A suspension of nitroaniline 7 (5.0 g, 16.5 mmol) in methanol wassparged with N₂ for 20 min after which 10% Pd/C (0.88 g, 0.8 mmol) wasadded. The reaction was purged with H₂ and maintained under a H₂atmosphere overnight at room temperature. The reaction was purged withN₂ and filtered through Celite. The collected solids were washed withEtOAc (3×50 mL), and the combined organic layers were dried (MgSO₄) andconcentrated to afford 4.35 g (16.0 mmol, 97%) of an off white solid as8: ¹H NMR (300 MHz, CDCl₃) δ 8.30 (d, J=5.5 Hz, 1 H), 7.99 (br s, 1 H),7.67 (d, J=2.5 Hz, 1 H), 6.91 (dd, J=2.5, 5.5 Hz, 1 H), 6.62 (d, J=8.5Hz, 1 H), 6.53 (dd, J=2.5, 8.5 Hz, 1 H), 6.44 (d, J=2.5 Hz, 1 H), 2.98(d, J=5.2 Hz, 3 H), 2.86 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃) δ 167.4,164.9, 152.2, 149.6, 146.0, 136.6, 136.3, 114.0, 112.3, 112.0, 110.2,109.0, 31.6, 26.5; mp 153-156° C. dec.; LCMS m/z 273.3 (MH⁺), t_(R)=1.66min.

[0163] Step 2. Synthesis of(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide:

[0164] A 250 mL round bottom flask was charged with4-bromophenylisothiocyanate (2.17 g, 10.1 mmol), diamine 8 (2.74 g, 10.1mmol), and MeOH (40 mL) and the reaction was maintained at rt overnight.Ferric chloride (2.43 g, 15 mmol) was added and the resulting redreaction mixture was stirred overnight. The reaction was partitionedwith EtOAc (100 mL) and water (100 mL), and filtered through Celite. Thelayers were separated and the aqueous phase was neutralized (pH=7) withsaturated Na₂CO₃ solution. The resulting aqueous phase was extractedwith EtOAc (100 mL) and the mixture was filtered through Celite. Thephases were separated and the aqueous phase was again extracted andfiltered. The combined organic layers were washed with brine (250 mL),dried (MgSO₄), and concentrated to give a brown solid. The crude residuewas purified by trituration in hot toluene to furnish 2.22 g (4.95 mmol,49%) of a tan solid as 1: ¹H NMR (300 MHz, CDCl₃) δ 8.38 (d, J=5.8 Hz, 1H), 8.07 (br d, J=4.7 Hz, 1 H), 7.61 (d,J=2.5 Hz, 1 H), 7.44 (app dd,J=8.8, 20.6 Hz, 4 H), 7.05 (m, 3 H), 6.78 (dd, J=2.2, 8.5 Hz, 1 H), 3.51(s, 3 H), 3.00 (d, J=5.2 Hz, 3 H); mp 251-254° C. dec.; LCMS m/z 452.2(MH⁺), t_(R)=2.17 min.

EXAMPLES 121-384

[0165] The compounds shown in the following Table 3 (Examples 121-384)were prepared from following the procedure described for Example 120a.TABLE 3 Ex- am- ple Structure Name MH+ 121

4-[(2-{[4-chloro-3-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-methylpyridine-2- carboxamide 476.1122

N-methyl-4-[(1-methyl-2-{[4- (trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 442 123

(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yl-oxy}(2-pyridyl))-N-methyl- carboxamide 452.0 124

(4-{2-[(4-chlorophenyl)amino]- 1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarbox- amide 408.1 125

(4-{2-[(4-indophenyl)amino]-1- methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide 500.1 126

N-methyl(4-{1-methyl-2-[(4- methylphenyl)amino]benzimidazol-5-yloxy}(2-pyridyl))carbox- amide 388.2 127

N-methyl(4-{1-methyl-2-[(4- phenoxyphenyl)amino]benzimidazol-5-yloxy}(2-pyridyl))- carboxamide 466.2 128

N-methyl[4-(1-methyl-2-{[4- (trifluoromethoxy)phenyl]amino}-benzimidazol-5-yloxy)(2- pyridyl)]carboxamide 458.2 129

(4-{2-[(4-butylphenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 430.2 130

(4-{2-[(4-bromo-3-fluoro- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))-N-methylcarboxamide 470.1 131

N-methyl(4-{1-methyl-2-[(4- nitrophenyl)amino]benzimidazol-5-yloxy}(2-pyridyl))- carboxamide 419.2 132

N-methyl[4-(1-methyl-2-{[4- (methylethyl)phenyl]amino}ben-zimidazol-5-yloxy)(2-pyridyl)]- carboxamide 416.3 133

(4-{2-[(3,4-dichlorophenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 442.1 134

(4-{2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))-N-methylcarboxamide 466.1 135

(4-{2-[(3,4-dimethylphenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 402.2 136

(4-{2-[(3-chloro-4-fluoro- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))-N-methylcarboxamide 426.1 137

methyl 4-({1-methyl-5-[2-(N- methylcarbamoyl)(4-pyridyl-oxy)]benzimidazol-2-yl}amino)- benzoate 432.2 138

(4-{2-[(4-bromo-3-chloro- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))-N-methylcarboxamide 486.0 139

(4-{2-[(3-bromophenyl)amino]- 1-methylbenzimidazol-5-yl-oxy}(2-pyridyl))-N-methyl- carboxamide 452.1 140

(4-{2-[(4-acetylphenyl)amino]- 1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarbox- amide 416.2 141

[4-(2-{[4-(tert-butyl)phenyl]- amino}-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methyl- carboxamide 430.2 142

(4-{2-[(4-methoxyphenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 404.2 143

(4-{2-[(4-cyclohexylphenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 456.2 144

(4-{2-[(3,4-difluorophenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 410.2 145

(4-{2-[(4-methoxy-2-methyl- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))-N-methylcarboxamide 418.2 146

(4-{2-[(3-chlorophenyl)amino]- 1-methylbenzimidazol-5-yl-oxy}(2-pyridyl))-N-methyl- carboxamide 408.1 147

(4-{2-[(3-fluorophenyl)amino]- 1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarbox- amide 392.2 148

4-({1-methyl-5-[2-(N-methyl- carbamoyl)(4-pyridyloxy)]-benzimidazol-2-yl}amino)- benzoic acid 418.2 149

N-methyl{4-[1-methyl-2- (phenylcarbonylamino)- benzimidazol-5-yloxy](2-pyridyl)}carboxamide 402.2 150

[4-(2-{[2-chloro-5-(trifluoro- methyl)phenyl]amino}-1-methylbenzimidazol-5-yloxy)(2- pyridyl)]-N-methylcarboxamide 476.1 151

(4-{2-[(2,5-dimethoxyphenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 434.2 152

(4-{2-[(2,4-difluorophenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 410.2 153

(4-{2-[(3,5-difluorophenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 410.2 154

(4-{2-[(4-ethylphenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 402.2 155

(4-{2-[(4-chlorophenyl)amino]- 1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarbox- amide 408.1 156

(4-{2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))-N-methylcarboxamide 466.1 157

(4-{2-[(2-methoxy-4-nitro- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))-N-methylcarboxamide 448.4 158

N-methyl[4-(1-methyl-2-{[2-(tri- fluoromethyl)phenyl]amino}ben-zimidazol-5-yloxy)(2-pyridyl)]- carboxamide 441.4 159

(4-{2-[(3-methoxyphenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 403.4 160

(4-{2-[(2-ethylphenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 401.4 161

(4-{2-[(2,5-difluorophenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 409.3 162

(4-{2-[(2,6-dichlorophenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl- carboxamide 442.3 163

(4-{2-[(4-ethylphenyl)amino]- benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 388.2 164

N-methyl(4-{1-methyl-2-[(2- methylthiophenyl)amino]-benzimidazol-5-yloxy}(2- pyridyl))carboxamide 420.1 165

N-methyl(4-{1-methyl-2-[(4- methylthiophenyl)amino]-benzimidazol-5-yloxy}(2- pyridyl))carboxamide 420.1 166

N-methyl[4-(1-methyl-2-{[2- (trifluoromethoxy)phenyl]-amino}benzimidazol-5-yloxy)(2- pyridyl)]carboxamide 458.1 167

[4-(2-{[2-fluoro-5-(trifluoro- methyl)phenyl]amino}-1-methylbenzimidazol-5-yloxy)(2- pyridyl)]-N-methylcarboxamide 460.1 168

(4-{2-[(4-cyanophenyl)amino]- 1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methyl- carboxamide 399.1 169

N-methyl[4-(1-methyl-2-{[3- (trifluoromethyl)phenyl]amino}-benzimidazol-5-yloxy)(2- pyridyl)]carboxamide 442.1 170

N-methyl[4-(1-methyl-2-{[2- (methylethyl)phenyl]amino}-benzimidazol-5-yloxy)(2- pyridyl)]carboxamide 416.2 171

(4-{2-[(5-chloro-2,4-dimethoxy- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))-N-methylcarboxamide 468.2 172

N-methyl(4-{1-methyl-2-[(2- phenylphenyl)amino]ben-zimidazol-5-yloxy}(2-pyridyl))- carboxamide 450.2 173

(4-{2-[(3-ethylphenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 402.2 174

(4-{2-[(2-fluorophenyl)amino]- 1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarbox- amide 392.1 175

(4-{2-[(4-bromophenyl)amino]- 1-ethylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 466.1 176

(4-{2-[(4-aminophenyl)amino]- 1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarbox- amide 389.2 177 (syn- the- sis as in Ex 1

N-methyl[4-(1-methyl-2-{[4- (methylamino)phenyl]amino}-benzimidazol-5-yloxy)(2- pyridyl)]carboxamide 403.2 178 (syn- the- sisas in Ex 1

[4-(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-benzimidazol-5-yloxy)(2- pyridyl)]-N-methylcarboxamide 417.2 179

N-methyl-4-[(1-methyl-2-{[5- methyl-2-(methyloxy)phenyl]-amino}-1H-benzimidazol-5- yl)oxy]pyridine-2-carboxamide 418.5 180

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 434.5 181

4-({2-[(2,6-difluorophenyl)- amino]-1-methyl-1H-ben-zimidazol-5-yl}oxy)-N-methyl- pyridine-2-carboxamide 410.4 182

4-[(2-{[3,5-bis(trifluoromethyl)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 510.4 183

N-methyl-4-[(1-methyl-2-{[4- (methyloxy)-1,1′-biphenyl-3-yl]-amino}-1H-benzimidazol-5-yl)- oxy]pyridine-2-carboxamide 480.5 184

4-({2-[(2,4-dimethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 402.5 185

4-({2-[(2-chloro-5-nitrophenyl)- amino]-1-methyl-1H-ben-zimidazol-5-yl}oxy)-N-methyl- pyridine-2-carboxamide 453.9 186

N-methyl-4-[(1-methyl-2-{[4- (methyloxy)-2-nitrophenyl]-amino}-1H-benzimidazol-5- yl)oxy]pyridine-2-carboxamide 449.4 187

4-[(2-{[4-chloro-2-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazoi-5-yl)- oxy]-N-methylpyridine-2- carboxamide 476.9188

4-({2-[(3-chloro-2-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 422.9 189

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 392.4 190

4-({2-[(2,3-dimethylphenyl)- amino]-1-methyl-1H-ben-zimidazol-5-yl}oxy)-N-methyl- pyridine-2-carboxamide 402.5 191

4-[(2-{[5-chloro-2-(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 438.9 192

N-methyl-4-[(1-methyl-2-{[4- (1,3-oxazol-5-yl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 441.5 193

4-[(2-{[2-(ethyloxy)phenyl]- amino}-1-methyl-1H-ben-zimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 418.5 194

4-({2-[(2-bromophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 453.3 195

4-{[2-(cyclohexylamino)-1- methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 380.5 196

N-methyl-4-({1-methyl-2-[(3- nitrophenyl)amino]-1H-ben-zimidazol-5-yl}oxy)pyridine-2- carboxamide 419.4 197

4-({2-[(3-cyanophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 399.4 198

N-methyl-4-[(1-methyl-2-{[4- (1H-pyrazol-1-yl)phenyl]-amino}-1H-benzimidazol-5-yl)- oxy]pyridine-2-carboxamide 440.5 199

4-({2-[(2-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 408.9 200

4-{[2-(cyclopropylamino)-1- methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 338.4 201

4-[(2-{[4-(ethyloxy)phenyl]- amino}-1-methyl-1H-ben-zimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 418.5 202

N-methyl-4-{[1-methyl-2-({3- [(phenylmethyl)oxy]phenyl}amino)-1H-benzimidazol-5-yl]oxy}- pyridine-2-carboxamide 480.5 203

4-{[2-(2,3-dihydro-1H-inden-5- ylamino)-1-methyl-1H-ben-zimidazol-5-yl]oxy}-N-methyl- pyridine-2-carboxamide 414.5 204

4-({2-[(2-ethyl-6-methylphenyl)- amino]-1-methyl-1H-ben-zimidazol-5-yl}oxy)-N-methyl- pyridine-2-carboxamide 416.5 205

N-methyl-4-{[1-methyl-2-({4- [(4-nitrophenyl)oxy]phenyl}-amino)-1H-benzimidazol-5-yl]- oxy}pyridine-2-carboxamide 511.5 206

4-({2-[(cyclohexylmethyl)- amino]-1-methyl-1H-ben-zimidazol-5-yl}oxy)-N-methyl- pyridine-2-carboxamide 394.5 207

4-[(2-{[4-bromo-3-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-methylpyridine-2- carboxamide 521.3208

4-{[2-({4-[(Z)-amino(imino)- methyl]phenyl}amino)-1-methyl-1H-benzimidazol-5- yl]oxy}-N-methylpyridine-2- carboxamide 416.5209

4-({2-[(1-acetyl-2,3-dihydro-1H- indol-6-yl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 457.5 210

4-[(2-{[4-fluoro-3-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-methylpyridine-2- carboxamide 460.4211

4-{[2-(cycloheptylamino)-1- methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 394.5 212

4-({2-[(3-acetylphenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 416.5 213

4-{[2-(bicyclo[2.2.1]hept-2- ylamino)-1-methyl-1H-ben-zimidazol-5-yl]oxy}-N-methyl- pyridine-2-carboxamide 392.5 214

N-methyl-4-[(1-methyl-2-{[2- (methyloxy)-5-(trifluoromethyl)-phenyl]amino}-1H-ben- zimidazol-5-yl)oxy]pyridine-2- carboxamide 472.4215

4-[(2-{[4-(1-hydroxyethyl)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 418.5 216

N-methyl-4-({1-methyl-2-[(2- pyrrolidin-1-ylethyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 395.5 217

N-methyl-4-({1-methyl-2-[(3- morpholin-4-ylpropyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 425.5 218

N-methyl-4-[(1-methyl-2-{[3-(2- oxopyrrolidin-1-yl)propyl]-amino}-1H-benzimidazol-5- yl)oxy]pyridine-2-carboxamide 423.5 219

N-methyl-4-[(1-methyl-2-{[2-(1- methylpyrrolidin-2-yl)ethyl]-amino}-1H-benzimidazol-5- yl)oxy]pyridine-2-carboxamide 409.5 220

N-methyl-4-({1-methyl-2-[(2- morpholin-4-ylethyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 411.5 221

4-[(2-{[2,4-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 434.5 222

1,1-dimethylethyl 3-{[1-methyl- 5-({2-[(methylamino)carbonyl]-pyridin-4-yl}oxy)-1H-ben- zimidazol-2-yl]amino}benzoate 474.5 223

3-{[1-methyl-5-({2-[(methyl- amino)carbonyl]pyridin-4-yl}-oxy)-1H-benzimidazol-2-yl]- amino}benzoic acid 418.4 224

4-({2-[(3,5-dimethylisoxazol-4- yl)amino]-1-methyl-1H-ben-zimidazol-5-yl}oxy)-N-methyl- pyridine-2-carboxamide 393.4 225

N-methyl-4-({1-methyl-2-[(5- methyl-3-phenylisoxazol-4-yl)-amino]-1H-benzimidazol-5-yl}- oxy)pyridine-2-carboxamide 455.5 226

N-methyl-4-[(1-methyl-2-{[2-(1- methyl-1,2,3,6-tetrahydro-pyridin-4-yl)phenyl]amino}-1H- benzimidazol-5-yl)oxy]pyridine-2-carboxamide 448.9 227

4-({2-[(4-chloro-1H-indazol-3- yl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 448.9 228

N-methyl-4-{[1-methyl-2-({[4- (methyloxy)phenyl]methyl}amino)-1H-benzimidazol-5-yl]oxy}- pyridine-2-carboxamide 418.5 229

4-({2-[(2,3-difluorophenyl)- amino]-1-methyl-1H-ben-zimidazol-5-yl}oxy)-N-methyl- pyridine-2-carboxamide 410.4 230

N-methyl-4-({1-methyl-2-[(2- morpholin-4-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 459.5 231

4-({2-[(3-iodophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 500.3 232

N-methyl-4-[(1-methyl-2- {[3,4,5-tris(methyloxy)phenyl]-amino}-1H-benzimidazol-5- yl)oxy]pyridine-2-carboxamide 464.5 233

N-methyl-4-({1-methyl-2- [(thien-2-ylmethyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 394.5 234

N-methyl-4-({1-methyl-2-[(3- thien-2-yl-1H-pyrazol-5-yl)-amino]-1H-benzimidazol-5- yl}oxy)pyridine-2-carboxamide 446.5 235

4-{[2-(1,3-benzodioxol-5-yl- amino)-1-methyl-1H-ben-zimidazol-5-yl]oxy}-N-methyl- pyridine-2-carboxamide 418.4 236

4-({2-[(2-iodophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2- carboxamide 500.3 237

4-({2-[(2,6-diethylphenyl)- amino]-1-methyl-1H-ben-zimidazol-5-yl}oxy)-N-methyl- pyridine-2-carboxamide 430.5 238

4-[(2-{[3-(1-hydroxyethyl)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 418.5 239

4-[(2-{[4-(1H-imidazol-1-yl)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 440.5 240

N-methyl-4-[(1-methyl-2-{[2- (phenyloxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 466.5 241

4-[(2-{[3,4-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 434.5 242

N-methyl-4-[(1-methyl-2-{[2- morpholin-4-yl-5-(trifluoro-methyl)phenyl]amino}-1H- benzimidazol-5-yl)oxy]pyridine- 2-carboxamide527.5 243

N-methyl-4-({1-methyl-2- [(tricyclo[3.3.1.1˜3,7˜]dec-1-ylmethyl)amino]-1H- benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 446.6244

4-({2-[1,1′-bi(cyclohexyl)-2- ylamino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 462.6 245

4-{[2-({[(1S,5S)-6,6-dimethyl- bicyclo[3.1.1]hept-2-yl]methyl}-amino)-1-methyl-1H- benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide 434.6 246

N-methyl-4-{[1-methyl-2- (tricyclo[3.3.1.1˜3,7˜]dec-1-ylamino)-1H-benzimidazol-5- yl]oxy}pyridine-2-carboxamide 432.5 247

N-methyl-4-({1-methyl-2-[(3- methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 388.4 248

4-[(2-{[5-fluoro-2-(1H-imidazol- 1-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 458.5 249

N-methyl-4-({1-methyl-2-[(5- phenyl-1H-pyrazol-3-yl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 440.5 250

4-{[2-({4-[(4-ethylpiperazin-1- yl)methyl]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]- oxy}-N-methylpyridine-2- carboxamide 500.6251

4-({2-[(1,3-dioxo-2,3-dihydro- 1H-isoindol-5-yl)amino]-1-methyl-1H-benzimidazol-5-yl}- oxy)-N-methylpyridine-2- carboxamide 443.4252

N-methyl-4-({1-methyl-2-[(3- oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-1H-benzimidazol-5- yl}oxy)pyridine-2-carboxamide 429.4 253

4-({2-[(4-bromophenyl)- (methyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 467.3 254

N-methyl-4-{[1-methyl-2- (naphthalen-2-ylamino)-1H-benzimidazol-5-yl]oxy}pyridine- 2-carboxamide 424.5 255

ethyl 1-methyl-5-({2-[(methyl- amino)carbonyl]pyridin-4-yl}-oxy)-1H-benzimidazol-2-yl- carbamate 370.4 256

4-[(2-{[3-(1H-imidazol-1-yl)- propyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 406.5 257

N-methyl-4-({1-methyl-2-[(2- methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 388.4 258

4-({2-[(2,6-dimethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 402.5 259

4-{[2-({2-[(difluoromethyl)- oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N- methylpyridine-2-carboxamide 440.4 260

4-[(2-{[2-(1,1-dimethylethyl)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 430.5 261

N-methyl-4-({1-methyl-2- [methyl(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 402.5 262

N-methyl-4-[(1-methyl-2-{[3- (methylthio)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 420.5 263

4-{[2-({4-cyano-2-[(trifluoro- methyl)oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5- yl]oxy}-N-methylpyridine-2- carboxamide 483.4264

N-methyl-4-({1-methyl-2-[(4- {1-[(phenylmethyl)amino]-ethyl}phenyl)amino]-1H- benzimidazol-5-yl}oxy)pyridine- 2-carboxamide507.6 265

4-{[2-(1H-indol-5-ylamino)-1- methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 413.5 266

N-methyl-4-{[1-methyl-2- (phenylamino)-1H-benzimidazol-5-yl]oxy}pyridine- 2-carboxamide 374.4 267

N-methyl-4-[(1-methyl-2-{[2- (phenylcarbonyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 478.5 268

4-{[2-({4-bromo-2-[(trifluoro- methyl)oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5- yl]oxy}-N-methylpyridine-2- carboxamide 537.3269

4-({2-[(2,4-dibromo-6-fluoro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 550.2 270

4-{[2-(1,3-dihydro-2 h-isoindol- 2-yl)-1-methyl-1H-benzimidazol-5-yl]oxy}-N- methylpyridine-2-carboxamide 400.5 271

4-{[2-(isoquinolin-1-ylamino)-1- methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 425.5 272

N-methyl-4-[(1-methyl-2-{[2- (1H-pyrazol-1-yl)phenyl]-amino}-1H-benzimidazol-5- yl)oxy]pyridine-2-carboxamide 440.5 273

4-{[2-(1H-indol-6-ylamino)-1- methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 413.5 274

methyl 4-{[1-methyl-5-({2- [(methylamino)carbonyl]pyridin-4-yl}oxy)-1H-benzimidazol-2- yl]amino}-3-[(trifluoromethyl)-oxy]benzoate 516.4 275

4-({2-[(2-cyanophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 399.4 276

N-methyl-4-[(1-methyl-2-{[2- (phenylthio)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 482.6 277

4-[(2-{[2-[(4-chlorophenyl)oxy]- 5-(trifluoromethyl)phenyl]-amino}-1-methyl-1H- benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide 569.0 278

N-methyl-4-[(1-methyl-2-{[2- [(4-methylphenyl)oxy]-5-(trifluoromethyl)phenyl]amino}- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 548.5 279

4-({2-[(4-chlorophenyl)amino]- 1,7-dimethyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 422.9 280

4-[(2-{[3-(1,1-dimethylethyl)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 430.5 281

4-({2-[(3-cyclohexylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 456.6 282

4-({2-[(2,5-dichlorophenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 443.3 283

N-methyl-4-[(1-methyl-2-{[2- {[2-(methyloxy)phenyl]oxy}-5-(trifluoromethyl)phenyl]amino}- 1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide 564.5 284

4-[(2-{[2-[(4-cyanophenyl)oxy]- 5-(trifluoromethyl)phenyl]-amino}-1-methyl-1H- benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide 559.5 285

4-({2-[(2,5-dimethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 402.5 286

4-({2-[(5-fluoro-2-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 406.4 287

4-({2-[(2-aminophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 389.4 288

4-({2-[(2-cyano-5-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 413.5 289

N-methyl-4-[(1-methyl-2-{[(4- methylphenyl)methyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 402.5 290

4-({2-[(4-bromo-2-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 467.3 291

4-({2-[(5-bromo-2-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 467.3 292

N-methyl-4-({1-methyl-2-[(4- methyl-1,1′-biphenyl-3-yl)-amino]-1H-benzimidazol-5-yl}- oxy)pyridine-2-carboxamide 464.5 293

4-({2-[(5-chloro-2-fluoro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 426.8 294

4-[(2-{[5-cyclohexyl-2-(methyl- oxy)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 486.6 295

4-({2-[(4-bromo-2-fluoro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 471.3 296

4-({2-[(2-amino-4-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 403.5 297

N-methyl-4-{[1-methyl-2- (5,6,7,8-tetrahydronaphthalen-1-ylamino)-1H-benzimidazol-5- yl]oxy}pyridine-2-carboxamide 428.5 298

N-methyl-4-[(1-methyl-2-{[4- (methylsulfonyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 452.5 299

N-methyl-4-{[1-methyl-2-({3- [(trifluoromethyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]- oxy}pyridine-2-carboxamide 474.5 300

N-methyl-4-{[1-methyl-2-({4- [(trifluoromethyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]- oxy}pyridine-2-carboxamide 474.5 301

4-{[2-(1,1′-biphenyl-3-ylamino)- 1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2- carboxamide 450.5 302

4-({2-[(2-chloro-4-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 422.9 303

4-[(2-{[2-bromo-4-(1-methyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 495.4 304

4-({2-[(3-ethynylphenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 398.4 305

4-{[2-(isoquinolin-7-ylamino)-1- methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 425.5 306

N-methyl-4-[(1-methyl-2-{[3-(1- methylethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 416.5 307

4-({2-[(3-bromo-4-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 467.3 308

N-methyl-4-({1-methyl-2- [(phenylsulfonyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 438.5 309

4-{[2-(9H-fluoren-1-ylamino)-1- methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 462.5 310

4-{[2-(9H-fluoren-2-ylamino)-1- methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 462.5 311

4-({2-[(2,2-difluoro-1,3- benzodioxol-5-yl)amino]-1-methyl-1H-benzimidazol-5-yl}- oxy)-N-methylpyridine-2- carboxamide 454.4312

N-methyl-4-{[1-methyl-2-({3- [(trifluoromethyl)oxy]phenyl}amino)-1H-benzimidazol-5-yl]- oxy}pyridine-2-carboxamide 458.4 313

N-methyl-4-({1-methyl-2-[(1- methylethyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 340.4 314

N-methyl-4-({1-methyl-2-[(2- phenylethyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 402.5 315

4-({2-[(3-cycloheptylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 470.6 316

N-methyl-4-[(1-methyl-2- {[(phenylmethyl)sulfonyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 452.5 317

4-{[2-(2,3-dihydro-1H-indol-6- ylamino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N- methylpyridine-2-carboxamide 415.5 318

N-methyl-4-[(1-methyl-2-{[1-(3- pyridin-4-ylpropanoyl)-2,3-dihydro-1H-indol-6-yl]amino}- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 548.6 319

4-({2-[(3-chloro-4-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 422.9 320

4-{[2-(cyclopentylamino)-1- methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2- carboxamide 366.4 321 (syn- the- sis as inEx 1)

4-[(2-{[4-(diethylamino)phenyl]- amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 445.5 322

N-methyl-4-[(1-methyl-2-{[2-(4- methylphenyl)ethyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 416.5 323

4-[(2-{[4-bromo-2-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-methylpyridine-2- carboxamide 521.3324

4-({2-[(4-chloro-2-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 422.9 325

4-[(2-{[3-(diethylamino)- propyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 411.5 326

4-({2-[(4-bromo-2-chloro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 487.8 327

4-({2-[(3,5-dimethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 402.5 328

4-({2-[(cyclopropylmethyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 352.4 329

4-{[2-(2,3-dihydro-1,4- benzodioxin-6-ylamino)-1-methyl-1H-benzimidazol-5-yl]- oxy}-N-methylpyridine-2- carboxamide 432.4330

N-methyl-4-[(1-methyl-2-{[4- (phenyloxy)pyridin-3-yl]-amino}-1H-benzimidazol-5-yl)- oxy]pyridine-2-carboxamide 467.5 331

N-methyl-4-({1-methyl-2-[(4- pyridin-2-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 451.5 332

4-({2-[(2-chloro-4-fluoro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 426.8 333

4-({2-[(4-fluoro-2-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 406.4 334

N-methyl-4-({1-methyl-2- [(2,4,5-trimethylphenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 416.5 335

4-[(2-{[2-chloro-4-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-methylpyridine-2- carboxamide 476.9336

4-({2-[(5-chloro-2-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 422.9 337

4-({2-[(4-chloro-2-fluoro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 426.8 338

N-methyl-4-[(1-methyl-2-{[3-(1- methylpropyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 430.5 339

4-({2-[(4-fluoro-3-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 406.4 340

4-({2-[(4-chloro-3-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 422.9 341

4-{[2-({3-bromo-4-[(trifluoro- methyl)oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5- yl]oxy}-N-methylpyridine-2- carboxamide 537.3342

4-{[2-({3-chloro-4-[(trifluoro- methyl)oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]- oxy}-N-methylpyridine-2- carboxamide 492.9343

N-methyl-4-({1-methyl-2-[(4- pyridin-3-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 451.5 344

4-[(2-{[3-chloro-4-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-methylpyridine-2- carboxamide 476.9345

4-({2-[(4-chloro-3-fluoro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 426.8 346

4-({2-[(2-bromo-4-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 467.3 347

N-methyl-4-({1-methyl-2- [(2,3,5-trifluorophenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 428.4 348

4-({2-[(2,4-dibromophenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 532.2 349

4-({2-[(2-chloro-5-fluoro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 426.8 350

4-{[2-({3-chloro-4-[(trifluoro- methyl)thio]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]- oxy}-N-methylpyridine-2- carboxamide 508.9351

4-({2-[(3-chloro-1H-indol-6- yl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 447.9 352

4-[(2-{[3,5-bis(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 486.6 353

4-[(2-{[5-(1,1-dimethylethyl)-2- (methyloxy)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-methylpyridine-2- carboxamide 460.5354

N-methyl-4-[(1-methyl-2-{[2- (methyloxy)-5-(1-methyl-1-phenylethyl)phenyl]amino}-1H- benzimidazol-5-yl)oxy]pyridine-2-carboxamide 522.6 355

4-[(2-{[4-chloro-2,5-bis(methyl- oxy)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 468.9 356

4-{[2-({4-fluoro-2-[(1-methyl- ethyl)oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]- oxy}-N-methylpyridine-2- carboxamide 450.5357

N-methyl-4-{[1-methyl-2-({3- [(1-methylethyl)oxy]phenyl}-amino)-1H-benzimidazol-5-yl]- oxy}pyridine-2-carboxamide 432.5 358 (syn-the- sis as in Ex 769)

4-({2-[(3-furan-3-ylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 440.5 359

4-[(2-{[4-chloro-5-methyl-2- (methyloxy)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-methylpyridine-2- carboxamide 452.9360

N-methyl-4-[(1-methyl-2-{[2- methyl-5-(1-methylethyl)- phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 430.5 361

4-[(2-{[2,5-bis(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 486.6 362

4-{[2-({5-chloro-2-[(difluoro- methyl)oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]- oxy}-N-methylpyridine-2- carboxamide 474.9363

N-methyl-4-{[1-methyl-2-({4- [(phenylmethyl)oxy]phenyl}amino)-1H-benzimidazol-5-yl]oxy}- pyridine-2-carboxamide 480.5 364

4-({2-[(2-{[cyclohexyl(methyl)- amino]methyl}phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}- oxy)-N-methylpyridine-2- carboxamide 499.6365

N-methyl-4-({1-methyl-2-[(6- pyrrolidin-1-ylpyridin-3-yl)-amino]-1H-benzimidazol-5-yl}- oxy)pyridine-2-carboxamide 444.5 366

4-[(2-{[6-(dimethylamino)- pyridin-3-yl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 418.4 367

N-methyl-4-({1-methyl-2-[(1- methylpiperidin-4-yl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 395.4 368

N-methyl-4-({1-methyl-2-[(4- methylcyclohexyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 394.4 369

4-({2-[(cycloheptylmethyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 408.5 370

N-methyl-4-({1-methyl-2- [(3,3,5-trimethylcyclohexyl)-amino]-1H-benzimidazol-5-yl}- oxy)pyridine-2-carboxamide 422.5 371

N-methyl-4-({1-methyl-2-[(2- methylcyclohexyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 394.4

EXAMPLE 372 Synthesis of4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-ethylpyridine-2-carboxamide

[0166] The compound4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-ethylpyridine-2-carboxamidewas synthesized as follows:

[0167] Step 1. Synthesis of tert-butyl 4-chloropyridine-2-carboxylate:

[0168] 4-chloropyridine-2-carbonyl chloride (1 eq) was suspended inanhydrous tetrahydrofuran. Then 2 equivalents of a solution of 1 Mpotassium tert-butoxide was added dropwise to the reaction slowly as thereaction was stirring under nitrogen. After 3-4hours or when thereaction was determined to be complete by HPLC, the reaction wasevaporated under reduced pressure and diluted with ethyl acetate. Theorganic layer was washed with water followed by brine and dried overanhydrous sodium sulfate. The organic extracts were evaporated underreduced pressure to yield the tert-butyl ester as a yellow oil. MS:MH+=214.0

[0169] Step 2. Synthesis of tert-butyl4-(4-amino-3-nitrophenoxy)pyridine-2-carboxylate:

[0170] Solid anhydrous white powdered KHMDS (2 eq) was suspended in asolution of dimethylformamide. Red crystalline 4-amino-3-nitrophenol (1eq) was charged to the rapidly stirring solution under an inertatmosphere and the heterogeneous solution was allowed to stir for 2hours. Then a dimethylformamide solution of tert-butyl4-chloropyridine-2-carboxylate (1 eq) was added dropwise. Anhydrouspowdered potassium carbonate (1.2 eq) was charged to the reaction as anacid scavenger. The purple colored viscous mixture was heated to 80° C.for 12-15 hours until when it was determined to be complete by HPLC. Thereaction was evaporated under reduced pressure and diluted with excessethyl acetate and water. An extraction of the aqueous layer was madewith ethyl acetate. The organic layers were combined and washed 4 timeswith water followed by brine. The organic layer was dried over anhydroussodium sulfate and evaporated under reduced pressure. The crude materialwas purified by flash silica gel chromatography using an eluent of 1:1mixture of hexanes to ethyl acetate to give the desired product. MS:MH+=332.

[0171] Step 3. Synthesis of tert-butyl4-[3-nitro-4-(2,2,2-trifluoroacetylamino)phenoxy]pyridine-2-carboxylate:

[0172] Trifluoroacetic anhydride (1 eq) was slowly added dropwise to asolution of the above amine in anhydrous methylene chloride undernitrogen. After 10-15 minutes or until the reaction was complete asdetermined by HPLC, the reaction was quenched with excess saturatedaqueous sodium bicarbonate. The product was extracted with methylenechloride from the aqueous layer and washed with water and brine. Theextracts were dried over anhydrous sodium sulfate and evaporated underreduced pressure to afford the title product as a yellow solid. MS:MH+=428.

[0173] Step 4. Synthesis of tert-butyl4-[3-nitro-4-(2,2,2-trifluoro-N-methylacetylamino)phenoxy]pyridine-2-carboxylate:

[0174] A solution of tert-butyl4-[3-nitro-4-(2,2,2-trifluoroacetylamino)phenoxy]pyridine-2-carboxylate(1 eq) and sodium carbonate (4 eq) in dimethylformamide was stirred at20° C. under nitrogen for thirty minutes before 2 equivalents ofiodomethane (2 eq) was charged slowly dropwise to the reaction. After2-3 hours or until it was determined to be complete by HPLC, thereaction was evaporated under reduced pressure. The crude mixture wasdiluted with ethyl acetate and washed with water. The organic layer wasdried over anhydrous sodium sulfate and evaporated under reducedpressure to afford the title product as an orange solid. MS: MH⁺=442.

[0175] Step 5. Synthesis of tert-butyl4-[4-(methylamino)-3-nitrophenoxy]pyridine-2-carboxylate:

[0176] A solution of tert-butyl4-[3-nitro-4-(2,2,2-trifluoro-N-methylacetylamino)phenoxy]pyridine-2-carboxylate in ethanol was stirred at roomtemperature. 1N sodium hydroxide was slowly dropped into the reactionuntil the conversion was complete by HPLC. The reaction was evaporatedunder reduced conditions and then extracted with ethyl acetate andwashed with a saturated aqueous solution of ammonium chloride followedby water and brine. The organic extracts were dried over anhydroussodium sulfate and evaporated under reduced pressure to afford theproduct as an orange solid. MS: MH⁺=346

[0177] Step 6. Synthesis of tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate:

[0178] A solution of tert-butyl4-[4-(methylamino)-3-nitrophenoxy]pyridine-2-carboxylate (1 eq) and 10%palladium on carbon (0.1 eq) in methanol was stirred at room temperatureand flushed with nitrogen. Hydrogen was flushed through the reaction for1-2 hours or until the reaction was determined to be complete by HPLC.Nitrogen was flushed through the reaction for 15 minutes before thereaction was filtered through a celite pad. The celite pad was washedwith excess methanol followed by concentration under reduced pressure toafford the product as a light yellow solid. MS: MH⁺=316.

[0179] Step 7. Synthesis of tert-butyl4-{2-[(4-bromophenyl)amino]-1-methyl-benzimidazol-5-yloxy}pyridine-2-carboxylate:

[0180] A solution of the diamine from step 6 (1 eq) and 4-bromophenylisothiocyanate (1 eq) in anhydrous tetrahydrofuran under nitrogen wasstirred at 20° C. for 2-3 hours or when determined to be complete byHPLC. The solution was treated With 3 equivalents of1-ethyl-(3-dimethylaminopropyl) carbodiimide HCl. The stirred solutionwas heated to 50° C. under nitrogen for 2-3 hrs or until the reaction isdetermined to be complete by HPLC. The reaction was evaporated underreduced pressure and then diluted with ethyl acetate and water. Theaqueous layer was back extracted with ethyl acetate. The combinedorganic layers were washed with water and brine. The organic layer wasdried over anhydrous sodium sulfate and later evaporated under reducedpressure. The crude material was purified by reverse high-pressureliquid chromatography to afford the product as a brown powder afterlyophilization. MS: MH⁺=495.

[0181] Step 8. Synthesis of4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yl-oxy}pyridine-2-carboxylicacid

[0182] A solution of the product of step 7 in trifluoroacetic acid wastreated with two drops of water at room temperature for 3-4 hours oruntil the reaction was determined to be complete by HPLC. The reactionwas evaporated under reduced pressure to afford the product as ared-orange oil in quantitative yield. MS: MH⁺=439.

[0183] Step 9. Synthesis of4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-ethylpyridine-2-carboxamide:

[0184] A solution of above (1 eq) in anhydrous tetrahydrofuran (0.5 ml)was treated with O-benzotriazol-1-yl N,N,N′,N′-tetramethyl uroniumhexafluorophosphate (2 eq), excess diisopropylethyl amine, and ethylamine (1 eq). The reaction was left stirring under nitrogen for 12-15hours. The reaction was evaporated under reduced pressure and dilutedwith ethyl acetate. The ethyl acetate layer was washed once with waterand then evaporated under reduced pressure. The crude material waspurified by reverse high-pressure liquid chromatography and recovered asTFA salt after lyophilization. MS: MH⁺=466.

EXAMPLES 373-447

[0185] The compounds shown in the following Table 4 (Examples 373-447)were prepared from following the procedure described for Example 372.TABLE 4 Example Structure Name MH+ 373

4-([{2-[(4-bromophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}-oxy)-N-(2-hydroxyethyl)pyridine- 2-carboxamide 482 374

4-({2-[(4-bromophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}-oxy)-N,N-dimethylpyridine-2- carboxamide 466 375

N-({2-[(4-bromophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}-oxy)-N-(2,2,2-trifluoroethyl)- pyridine-2-carboxamide 521 376

N-(4-bromophenyl)-1-methyl-5- {[2-(pyrrolidin-1-ylcarbonyl)-pyridin-4-yl]oxy}-1H- benzimidazol-2-amine 492 377

ethyl (3R)-3-(methyloxy)-4-[({4- [(2-{[4-(trifluoromethyl)phenyl]-amino}-1H-benzimidazol-5- yl)oxy]pyridin-2-yl}carbonyl)-amino]piperidine-1-carboxylate 599 378

4-({2-[(4-bromophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(dimethylamino)- ethyl]pyridine-2-carboxamide 509 379

4-({2-[(4-bromophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}-oxy)-N-(tetrahydrofuran-2-yl- methyl)pyridine-2-carboxamide 522 380

4-({2-[(4-bromophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}-oxy)-N-(2-morpholin-4-ylethyl)- pyridine-2-carboxamide 551 381

4-({2-[(4-bromophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}-oxy)-N-(piperidin-4-ylmethyl)- pyridine-2-carboxamide 535 382

5-({2-[(3-aminopyrrolidin-1-yl)- carbonyl]pyridin-4-yl}oxy)-N-(4-bromophenyl)-1-methyl-1H- benzimidazol-2-amine 507 383

4-({2-[(4-bromophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}-oxy)-N-[1-(diphenylmethyl)- azetidin-3-yl]pyridine-2- carboxamide 659384

N-((3S)pyrrolidin-3-yl)(4-{2-{(4- bromophenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))carboxamide 507.0 385

N-(2-aminoethyl)(4-{2-[(4-bromo- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))carboxamide 481.0 386

N-((3R)pyrrolidin-3-yl)(4-{2-[(4- bromophenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))carboxamide 507.0 387

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-piperidylethyl)- carboxamide 549.1 388

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(oxolan-2-ylmethyl)- carboxamide 522.0 389

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-pyrrolidinylethyl)- carboxamide 535.1 390

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(1,3-thiazol-2-yl)- carboxamide 521.0 391

3-aminopyrrolidinyl 4-{2-[(4- bromophenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2-pyridyl) ketone 507.0 392

N-[(3R,5R)-5-(methoxymethyl)- pyrrolidin-3-yl](4-{2-[(4-bromo-phenyl)amino]-1-methyl- benzimidazol-5-yloxy}(2- pyridyl))carboxamide551.1 393

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[(1-ethylpyrrolidin-2- yl)methyl]carboxamide 549.2 394

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(3-piperidyl)- carboxamide 521.0 395

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(3-imidazolylpropyl)- carboxamide 546.4 396

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[3-(2-oxo- pyrrolidinyl)propyl]carboxamide 563.4 397

4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}-pyridine-2-carboxamide 438.1 398

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(methylethyl)- carboxamide 480.3 399

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(4-hydroxy- cyclohexyl)carboxamide 536.4 400

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-methoxyethyl)- carboxamide 496.3 401

N-(2h-benzo[d]1,3-dioxolen-5- ylmethyl)(4-{2-[(4-bromophenyl)-amino]-1-methylbenzimidazol-5- yloxy}(2-pyridyl))carboxamide 572.4 402

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(4-pyridylmethyl)- carboxamide 529.3 403

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-(4-pyridyl)ethyl)- carboxamide 543.4 404

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[3-(4-methyl- piperazinyl)propyl]carboxamide 578.5 405

4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2- pyridyl)4-(2-oxyethyl)piperazinyl ketone 551.4 406

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-imidazol-4- ylethyl)carboxamide 532.4 407

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(1-methyl- pyrrolidin-2-yl)ethyl]carboxamide 549.1 408

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-oxoazaperhydro- epin-3-yl)carboxamide 549.1 409

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-indol-3-ylethyl)- carboxamide 581.4 410

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-piperidylcarboxamide 521.1 411

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(2-methoxyphenyl)- ethyl]carboxamide 572.1 412

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(3-methoxyphenyl)- ethyl]carboxamide 572.4 413

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(4-methoxyphenyl)- ethyl]carboxamide 572.4 414

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(4-methylpiperazinyl)- carboxamide 536.1 415

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-(4-piperidyl)ethyl)- carboxamide 549.4 416

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(phenylamino)- ethyl]carboxamide 557.4 417

N-{2-[(4-{2-[(4-bromophenyl)- amino]-1-methylbenzimidazol-5-yloxy}-2-pyridyl)carbonylamino]- ethyl}acetamide 523.4 418

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(2-oxo- imidazolidinyl)ethyl]carboxamide 550.4 419

methyl 2-[(4-{2-[(4-bromophenyl)- amino]-1-methylbenzimidazol-5-yloxy}-2-pyridyl)carbonylamino]- acetate 510.3 420

methyl (2S)-2-[(4-{2-[(4-bromo- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))carbonylamino]-3- methylbutanoate552.4 421

(2S)-2-[(4-{2-[(4-bromo- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))carbonylamino]-3- carbamoylpropanoicacid 553.3 422

methyl 3-[(4-{2-[(4-bromo- phenyl)amino]-1-methyl-benzimidazol-5-yloxy}-2-pyridyl)- carbonylamino]propanoate 524.3 423

N-((2S)-2-aminopropyl)(4-{2-[(4- bromophenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))carboxamide 495.3 424

N-((2R)-2-aminopropyl)(4-{2-[(4- bromophenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))carboxamide 495.3 425

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(pyrrolidin-2-yl- methyl)carboxamide 521.4 426

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-propylcarboxamide 480.3 427

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-6-yloxy}(2-pyridyl))-N-methylcarboxamide 452.1 428

2-[(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}-2-pyridyl)carbonylamino]acetic acid 496.31 429

(2S)-2-[(4-{2-[(4-bromophenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))carbonylamino]- 3-methylbutanoic acid 538.1 430

3-[(4-{2-[(4-bromophenyl)amino]- 1-methylbenzimidazol-5-yloxy}-2-pyridyl)carbonylamino]propanoic acid 510.1 431

(4-{2-[(4-bromophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(1-methyl(4- piperidyl))carboxamide 535.1 432

(4-{2-[(4-chlorophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(3-methoxypropyl)- carboxamide 466.1 433

(4-{2-[(4-chlorophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(3-imidazolylpropyl)- carboxamide 502.1 434

(4-{2-[(4-chlorophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-morpholin-4-yl- ethyl)carboxamide 507.2 435

(4-{2-[(4-chlorophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-piperidylethyl)- carboxamide 505.2 436

(4-{2-[(4-chlorophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(3-morpholin-4-yl- propyl)carboxamide 521.2 437

(4-{2-[(4-chlorophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[3-(2-oxo- pyrrolidinyl)propyl]carboxamide 519.2 438

(4-{2-[(4-chlorophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[(1-ethylpyrrolidin-2- yl)methyl]carboxamide 505.2 439

N-((3R)pyrrolidin-3-yl)(4-{2-[(4- chlorophenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))carboxamide 463.2 440

N-{2-[(4-{2-[(4-chlorophenyl)- amino]-1-methylbenzimidazol-5-yloxy}-2-pyridyl)carbonylamino]- ethyl}acetamide 479.2 441

(4-{2-[(4-chlorophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-imidazol-4-yl- ethyl)carboxamide 488.2 442

(4-{2-[(4-chlorophenyl)amino]-1- methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(1-methyl- pyrrolidin-2-yl)ethyl]carboxamide 505.2 443

N-[(3R,5R)-5-(methoxymethyl)- pyrrolidin-3-yl](4-{2-[(4-chloro-phenyl)amino]-1-methyl- benzimidazol-5-yloxy}(2- pyridyl))carboxamide507.2 444

(2S)-2-[(4-{2-[(4-chlorophenyl)- amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))carbonylamino]- propanoic acid 466.1 445

N-(2,3-dihydroxypropyl)(4-{2-[(4- chlorophenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))carboxamide 468.1 446

N-((3S)pyrrolidin-3-yl)(4-{2-[(4- chlorophenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2- pyridyl))carboxamide 463.2 447 (synthesis as inEx 120a)

(4-{2-[(2-methoxyphenyl)amino]- 1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide 404.1 448 (synthesis as in Ex 483)

4-[(2-{[3-(2-fluoropyridin-4-yl)-4- methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2- (4-methylpiperazin-1-yl)ethyl]-pyridine-2-carboxamide 595.7 448 (synthesis as in Ex 483)

4-[(2-{[3-(2-fluoropyridin-4-yl)-4- methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2- pyrrolidin-1-ylethyl)pyridine-2-carboxamide 566.7

EXAMPLE 450 Preparation of(4-Chloro-phenyl)-{5-[2-(4,5-dihydro-1H-imidazol-2-yl)-pyridin-4-yloxy]-1-methyl-1H-benzoimidazol-2-yl}-amine)

[0186] Step 1. Synthesis of4-(4-Amino-3-nitro-phenoxy)=puridine-2-carbonitrile:

[0187] Potassium carbonate (9.00 g) was dried in vacuo with heating,cooled to RT under nitrogen. 4-amino-3-ntrophenol (3.355 g),4-chloro-2-cyanopyridine (3.00 g) and DMSO (30 mL, anhydrous) wereadded. The system was stirred under nitrogen as it was heated to 103°C., and held at this temperature 1 hr. The reaction was then cooled toRT, poured onto ice/H₂O (500 mL) the precipitate was collected, washed(H₂O), dissolved (EtOAc), dried (Na₂SO₄), filtered and stripped to asolid. This was suspended (Et₂O), collected, air-dried 4.1015 g (73.5%)a second crop was collected (0.5467 gm, 10%). M/z=257 (M+1)

[0188] Step 2. Synthesis ofN-[4-(2-Cyano-pyridin-4-yloxy)-2-nitro-phenyl]-2,2,2-trifluoro-N-methyl-acetamide:

[0189] Potassium carbonate (1.6 g) was dried in vacuo with heating,cooled to RT and suspended in dichloromethane (30 mL) with4-(4-amino-3-nitro-phenoxy)=puridine-2-carbonitrile (2.005 gm) undernitrogen. This was cooled to 0° C. and TFAA (2.2 mL) was added, neat.The starting material goes into solution rapidly as addition is made.After 10 min at 0° C., the mixture was diluted with dichloromethane,washed (H₂O, aq NaCl), dried (K₂CO₃), filtered and stripped to a yellowfoam. M/z=353 (M+1) The product was used without purification.

[0190] Iodomethane (0.53 mL) was added to a suspension of potassiumcarbonate (1.858 g) in DMF (30 mL containing compound 2 (˜7.8 mmole)under nitrogen. The suspension stirred at RT overnight, then poured ontoH₂O (300 mL), extracted (Et₂O, 3×150 mL), the combined extracts werewashed (H₂O, aq. NaCl), dried (potassium carbonate), filtered andstripped to an orange oil (7.4922 g). M/z=367 (M+1)

[0191] Step 3. Synthesis of4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carbonitrile:

[0192] NaOH (1 mL, 1N aq) was added dropwise to a solution ofN-[4-(2-cyano-pyridin-4-yloxy)-2-nitro-phenyl]-2,2,2-trifluoro-N-methyl-acetamide(440 mg) in ethanol (6 mL) at RT. After 40 min, the mixture was dilutedwith H₂O (20 mL) and cooled to 0° C. Bright orange crystals werecollected, washed (H2O) and air-dried 311.1 mg (94%). M/z=271 (M+1)

[0193] Step 4. Synthesis of4-[2-(4-Chloro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carbonitrile:

[0194] Palladium on carbon (46 mg 10% w/w) was suspended in MeOH (2 mL)under nitrogen. The resulting suspension was added, under nitrogen, to asuspension of 4-(4-methylamino-3-nitro-phenoxy)-pyridine-2-carbonitrile(311 mg) in MeOH (3 mL) at RT. The atmosphere was exchanged withhydrogen, and the system stirred vigorously under 1 atm hydrogen for 1hr. The atmosphere was then exchanged for nitrogen, the mixture wasfiltered (celite) and the filtrate was used without further purificationin the next reaction. M/z=2421 (M+1).

[0195] 4-chlorophenylisothiocyanate (200 mg) was added to a solution ofcompound 5 in MeOH (10 mL). The solution was stirred at reflux for 2hrs. Iodomethane (71 microliters) was added, and stirring continued at67° C., overnight. The mixture was then cooled to RT evaporated todryness, and the residue chromatographed (0.5% NH₄OH, 5% MeOH, 94.5%dichloromethane on silica gel) to isolate a compound of Rf=0.29 (325mg). This was crystallized from dichloromethane/ether to give 127 mg.M/z=376 (M+1)

[0196] 1HNMR (MeOH-d4)

[0197] 9.40 ppm s(b) (1H)

[0198] 8.55 ppm d,d H=5.7, 0.6 Hz (1H)

[0199] 7.62 ppm m (2 h)

[0200] 7.42 ppm d,d J=2.5, 0.6 Hz (1H)

[0201] 7.43 ppm d (1H)

[0202] 7.37 ppm m (2 h)

[0203] 7.21 ppm d J=2.0 Hz (1H)

[0204] 7.15 ppm d,d J=5.9, 2.5 Hz (1H)

[0205] 6.97 ppm d,d J=8.4,2.2 hz (1H)

[0206] 3.80 ppm s (3H)

[0207] Step 5. Synthesis of(4-Chloro-phenyl)-{5-[2-(4,5-dihydro-1H-imidazol-2-yl)-pyridin-4-yloxy]-1-methyl-1H-benzoimidazol-2-yl}-amine:

[0208] H₂SO₄ (454 mg) was added cautiously to a suspension of4-[2-(4-chloro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carbonitrile(60.0 mg) in ethylenediamine (0.50 mL). The system was shaken at roomtemperature for 72 hrs, then poured onto ice/NaHCO₃. The solid productwas collected, washed (H₂O) air-dried 59.8 mg. M/z=419 (M+1).

EXAMPLE 451 Synthesis of(4-{2-[(4-bromophenyl)amino]benzoxazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide

[0209] Step 1. Synthesis of ²-amino-4-methoxyphenol

[0210] The mixture containing 4-methoxy-2-nitrophenol in methanol withcatalytic amount of 1I0% Pd/C was hydrogenated until disappearance ofyellow color to yield 2-amino-4-methoxyphenol. MS: MH+=140.

[0211] Step 2. Synthesis of 5-methoxybenzoxazole-2-thiol

[0212] The mixture containing 2-amino-4-methoxyphenol(1 eq) andO-ethylxanthic acid, potassium salt (1.1 eq) in pyridine was refluxedfor two hours. The resultant mixture was poured in to ice/watercontaining hydrochloric acid to yield a 5-methoxybenzoxazole-2-thiol asa tan solid. MS: MH+=182

[0213] Step 3. Synthesis of 2-chloro-5-methoxybenzoxazole

[0214] The mixture containing 5-methoxybenzoxazole-2-thiol was heated inthionyl chloride with a drop of DMF. The resultant mixture wasconcentrated and partitioned between ethyl acetate and water. Theorganic layer was washed with brine and dried and concentrated.Purification on a silica gel column gave 2-chloro-5-methoxybenzoxazoleas a white solid. MS: MH+=184.

[0215] Step 4. Synthesisof(4-bromophenyl)(5-methoxybenzoxazol-2-yl)amine

[0216] The mixture containing 2-chloro-5-methoxybenzoxazole(1 eq),4-bromoaniline (2 eq) and diisopropylethylamine was refluxed indimethylformamide. The resultant mixture was concentrated andpartitioned between ethyl acetate and water. The organic layer waswashed with brine and dried. Purification on silica gel gave(4-bromo-phenyl)(5-methoxybenzoxazol-2-yl)amine. MS: MH+=318

[0217] Step 5. Synthesis of 2-[(4-bromophenyl)amino]benzoxazol-5-ol

[0218] The mixture of (4-bromophenyl)(5-methoxybenzoxazol-2-yl)amine andhydrobromic acid (48%) was subjected to the microwave at 150° C. for6mins to yield 2-[(4-bromophenyl)amino]benzoxazol-5-ol. MS: MH+=305

[0219] Step 6. Synthesis of(4-{2-[(4-bromophenyl)amino]benzoxazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide

[0220] The mixture containing 2-[(4-bromophenyl)amino]benzoxazol-5-ol (1eq), potassium bis(trimethylsilyl)amide (4 eq), was stirred indimethylformamide for 30 min at room temperature. To this mixture wasadded (4-chloro(2-pyridyl)-N-methyl-carboxamide (1 eq) and Potassiumcarbonate (1.2 eq) and microwaved for 6 mins at 150° C. The reactionmixture was then concentrated and partitioned between ethyl acetate andwater. The organic layer was separated and washed with brine, dried,filtered and concentrated. Purification on Prep LC yielded the desiredproduct. MS: MH+=439.

[0221] The compounds shown in the following Table 5 (Examples 452-481)were prepared from following the procedure described for Examples449-451. TABLE 5 Example Structure Name MH+ 452

N-(2-aminoethyl)-4-({2-[(4-bromo- phenyl)amino]-1,3-benzoxazol-5-yl}oxy)pyridine-2-carboxamide 469.3 453

4-({2-[(4-bromophenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-(2-morpholin-4-ylethyl)pyridine-2- carboxamide 539.4 454

4-({2-[(4-bromophenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-[(3R)-pyrrolidin-3-yl]pyridine-2- carboxamide 495.3 455

4-({2-[(4-bromophenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-{(3R,5R)-5-[(methyloxy)methyl]pyrrolidin-3- yl}pyridine-2-carboxamide 539.4 456

4-({2-[(4-chlorophenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 395.8 457

4-({2-[(3,5-difluorophenyl)amino]- 1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 397.4 458

N-methyl-4-[(2-{[2-(trifluoro- methyl)phenyl]amino}-1,3-benzoxazol-5-yl)oxy]pyridine-2- carboxamide 429.4 459

4-({2-[(2-fluorophenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 379.4 460

4-({2-[(2,6-difluorophenyl)amino]- 1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 397.4 461

N-methyl-4-[(2-{[3-(trifluoro- methyl)phenyl]amino}-1,3-benzoxazol-5-yl)oxy]pyridine-2- carboxamide 429.4 462

4-({2-[(2-chlorophenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 395.8 463

4-({2-[(2-ethylphenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 389.4 464

N-methyl-4-[(2-{[4-(1-methyl- ethyl)phenyl]amino}-1,3-benzoxazol-5-yl)oxy]pyridine-2- carboxamide 403.5 465

4-({2-[(3-chlorophenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 395.8 466

N-methyl-4-{[2-({4-[(trifluoro- methyl)oxy]phenyl}amino)-1,3-benzoxazol-5-yl]oxy}pyridine-2- carboxamide 445.4 467

N-methyl-4-[(2-{[2-(1-methyl- ethyl)phenyl]amino}-1,3-benz-oxazol-5-yl)oxy]pyridine-2- carboxamide 403.5 468

4-({2-[(3,4-dichlorophenyl)amino]- 1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 430.3 469

4-({2-[(4-ethylphenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 389.4 470

4-[(2-{[4-(1-methylethyl)phenyl]- amino}-1,3-benzoxazol-5-yl)oxy]-N-[(3R)-pyrrolidin-3-yl]pyridine-2- carboxamide 458.5 471

4-({2-[(2,5- dimethylphenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 389.4 472

4-({2-[(4-bromophenyl)(methyl)- amino]-1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 454.3 473

N-methyl-4-{[2-(phenylamino)-1,3- benzoxazol-5-yl]oxy}pyridine-2-carboxamide 361.4 474

4-[(2-{[4-(dimethylamino)phenyl]- amino}-1,3-benzoxazol-5-yl)oxy]-N-methylpyridine-2-carboxamide 404.4 475

4-[(2-{[4-(4-ethylpiperazin-1-yl)- phenyl]amino}-1,3-benzoxazol-5-yl)oxy]-N-methylpyridine-2- carboxamide 473.5 476

4-({2-[(4-butylphenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 417.5 477

N-methyl-4-[(2-{[4-(phenyloxy)- phenyl]amino}-1,3-benzoxazol-5-yl)oxy]pyridine-2-carboxamide 453.5 478

4-[(2-{[4-(1-methylethyl)phenyl]- amino}-1,3-benzoxazol-5-yl)oxy]-N-(2-morpholin-4-ylethyl)pyridine- 2-carboxamide 502.6 479

N-[1-(1-methylethyl)azetidin-3-yl]- 4-[(2-{[4-(1-methylethyl)phenyl]-amino}-1,3-benzoxazol-5-yl)oxy]- pyridine-2-carboxamide 486.6 480

4-({2-[(4-bromo-3-fluorophenyl)- amino]-1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 458.3 481

4-[(2-{[4-(1-methylethyl)phenyl]- amino}-1,3-benzoxazol-5-yl)oxy]-N-[2-(2-oxoimidazolidin-1-yl)- ethyl]pyridine-2-carboxamide 501.6

EXAMPLE 482 Synthesis of [4-(2-{[4-(dimethylamino)phenyl]amino 1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide

[0222] Step 1. Synthesis of4-(2-{[4-(dimethylamino)phenylamino)-1-methyl-benzimidazol-5-yloxy)pyridinr-2-carboxylicacid

[0223] Totert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1eq) in methanol was added 4-(dimethylamino)benzeneisothiocyanate (1 eq)and stir at ambient temperature for 16 h. Formation of the correspondingthiourea was followed by LC/MS. The mixture was then concentrated and toit was added tetrahydrofuran and1-ethyl-(3-dimethylaminopropyl)carbodiimidehydrochloride (2 eq) and stirat ambient temperature for 16 h.tert-butyl4-(2-{[4-dimethylamino)phenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylatecrashes out of the reaction mixture. To it in methylene chloride wasadded trifluoroacetic acid and stirred at ambient temperature overnight.Resulting4-(2-{[4-dimethylamino)phenylamino)-1-methylbenzimidazol-5-yloxy)-pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH⁺=403.

[0224] Step 2. Synthesis of[4-(2-{[4-(dimethylamino)phenylamino-1-methyl-benzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide:

[0225] To4-(2-{[4-(dimethylamino)phenylamino)-1-methylbenzimidazol-5-yloxy)-pyridine-2-carboxylicacid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir atambient temperature for 16 h. The mixture was then concentrated andpartitioned between ethyl acetate and water. The organic layer wasconcentrated and preparative chromatography yielded[4-(2-{[4-(dimethylamino)phenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide.MS: MH⁺=498.

EXAMPLE 483 Synthesis of [4-(2-{[4-bromo-3-methylphenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide

[0226] Step 1. Synthesis of4-{2-[(4-bromo-3-methylphenyl)amino]-1-methyl-benzimidazol-5-yloxy)pyridine-2-carboxylicacid

[0227] Totert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1eq) in methanol was added 4-bromo-3-methylbenzeneisothiocyanate (1 eq)and stir at ambient temperature for 16 h. Formation of the correspondingthiourea was followed by LC/MS. To it was then added iodomethane (1 eq)and heated to 60° C. for 2 h. Formation oftert-butyl4-(2-{[4-bromo-3-methylphenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride wasadded trifluoroacetic acid and stirred at ambient temperature overnight.Resulting4-(2-{[4-bromo-3-methylphenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH⁺=452

[0228] Step 2. Synthesis of[4-(2-{[4-bromo-3-methylphenyl)amino-1-methyl-benzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide

[0229] To4-(2-{[4-bromo-3-methylpheylamino)-1-methylbenzimidazol-5-yloxy)-pyridine-2-carboxylicacid(1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2 eq),HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambienttemperature for 16 h. The mixture was then concentrated and partitionedbetween ethyl acetate and water. The organic layer was concentrated andpreparative chromatography yielded[4-(2-{[4bromo-3-methylphenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide.MS: MH⁺=549.

EXAMPLE 484 Synthesis of[4-(2-{[2-fluoro-5-(trifluoromethyl)phenyl)amino-1-methyl-benzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide

[0230] Step 1. Synthesis of4-{2-[(2-fluoro-5-(trifluoromethyl)phenyl)amino]-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid

[0231] Totert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1eq)in methanol was added 2-fluoro-5-(trifluoromethyl)benzeneisothiocyanate(1 eq) and stir at ambient temperature for 16 h. Formation of thecorresponding thiourea was followed by LC/MS. To it was then addediodomethane (1 eq) and heated to 60° C. for 2 h. Formation oftert-butyl4-(2-{[2-fluoro-5-(trifluoromethyl)phenyl)amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylatewas followed by LC/MS. To it in methylene chloride was addedtrifluoroacetic acid and stirred at ambient temperature overnight.Resulting4-(2-{[2-fluoro-5-(trifluoromethyl)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH⁺=446.

[0232] Step 2. Synthesis of[4-(2-{[2-fluoro-5-(trifluoromethyl)phenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide:

[0233] To4-(2-{[2-fluoro-5-(trifluoromethyl)phenylamino)-1-methylbenzimidazol-5-yl-oxy)pyridine-2-carboxylicacid (1 eq) in tetrahydrofuran was added 2-pyrrolidinyl-ethylamine (2eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir atambient temperature for 16 h. The mixture was then concentrated andpartitioned between ethyl acetate and water. The organic layer wasconcentrated and preparative chromatography yielded[4-(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino-l-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide.MS: MH⁺=542.

EXAMPLE 485 Synthesis of[4-(2-{[4-bromo-3-fluorophenyl)amino-1-methyl-benzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamide

[0234] Step 1. Synthesis of4-{2-[(4-bromo-3-fluorophenyl)amino]-1-methyl-benzimidazol-5-yloxy)pyridine-2-carboxylicacid

[0235] Totert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1eq) in methanol was added 4-bromo-3-fluorobenzeneisothiocyanate (1 eq)and stir at ambient temperature for 16 h. Formation of the correspondingthiourea was followed by LC/MS. To it was then added iodomethane (1 eq)and heated to 60° C. for 2 h. Formation oftert-butyl4-(2-{[4-bromo-3-fluorophenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylatewas followed by LC/MS. To it in methylene chloride was addedtrifluoroacetic acid and stirred at ambient temperature overnight.Resulting4-(2-{[4-bromo-3-fluorophenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH⁺=456.

[0236] Step 2. Synthesis of[4-(2-{[4-bromo-3-fluorophenyl)amino-1-methyl-benzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamide:

[0237] To4-(2-{[4-bromo-3-fluoropheylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid (1 eq) in tetrahydrofuran was added 2-piperidylethylamine (2 eq),HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambienttemperature for 16 h. The mixture was then concentrated and partitionedbetween ethyl acetate and water. The organic layer was concentrated andpreparative chromatography yielded[4-(2-{[4-bromo-3-fluorophenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)-carboxamide.MS: MH⁺=567.

EXAMPLE 486 Synthesis of4-{1-methyl-2-[(4-methylphenyl)amino-1-methyl-benzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide

[0238] Step 1. Synthesis of4-{1-methyl-2-[(4-methylphenyl)amino]benzimidazol-5-yloxy)pyridine-2-carboxylicacid

[0239] Totert-butyl-4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1eq) in methanol was added 4-methylbenzeneisothiocyanate (1 eq) and stirat ambient temperature for 16 h. Formation of the corresponding thioureawas followed by LC/MS. To it was then added iodomethane (1 eq) andheated to 60° C. for 2 h. Formation oftert-butyl-4-{1-methyl-2-[(4-methylphenyl)amino)benzimidazol-5-yloxy)pyridine-2-carboxylatewas followed by LC/MS. To it in methylene chloride was addedtrifluoro-acetic acid and stirred at ambient temperature overnight.Resulting4-{1-methyl-2-[(4-methylphenyl)amino]benzimidazol-5-yloxy)pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH⁺=374.

[0240] Step 2. Synthesis of4-{1-methyl-2-[(4-methylphenyl)amino-1-methyl-benzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide

[0241] To4-{1-methyl-2-[(4-methylphenyl)amino]benzimidazol-5-yloxy)pyridine-2-carboxylicacid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir atambient temperature for 16 h. The mixture was then concentrated andpartitioned between ethyl acetate and water. The organic layer wasconcentrated and preparative chromatography yielded4-{1-methyl-2-[(4-methylphenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-2(2-pyrrolidinylethyl)carboxamide.MS: MH⁺=470.

EXAMPLE 487 Synthesis of [4-(2-{[4-ethylphenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide

[0242] Step 1. Synthesis of4-{2-[(4-ethylphenyl)amino]-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid

[0243] Totert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1eq) in methanol was added 4-ethylbenzeneisothiocyanate (1 eq) and stirat ambient temperature for 16 h. Formation of the corresponding thioureawas followed by LC/MS. To it was then added iodomethane (1 eq) andheated to 60° C. for 2 h. Formation oftert-butyl4-(2-{[4-ethylphenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride wasadded trifluoroacetic acid and stirred at ambient temperature overnight.Resulting4-(2-{[4-ethylphenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH⁺=388.

[0244] Step 2. Synthesis of[4-(2-{[4-ethylphenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide

[0245] To4-(2-{[4-ethylpheylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir atambient temperature for 16h. The mixture was then concentrated andpartitioned between ethyl acetate and water. The organic layer wasconcentrated and preparative chromatography yielded[4-(2-{[4-ethylphenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinyl-ethyl)carboxamide.MS: MH⁺=484.

EXAMPLE 488 Synthesis of[4-(2-{[3-(tert-butyl)phenyl)amino-1-methyl-benzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamide

[0246] Step 1. Synthesis of4-{2-[(3-(tert-butyl)phenyl)amino]-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid

[0247] Totert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1eq) in methanol was added 3-(tert-butyl)benzeneisothiocyanate (1 eq) andstir at ambient temperature for 16 h. Formation of the correspondingthiourea was followed by LC/MS. To it was then added iodomethane (1 eq)and heated to 60° C. for 2 h. Formation oftert-butyl4-(2-{[3-(tert-butyl)phenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylatewas followed by LC/MS. To it in methylene chloride was addedtrifluoroacetic acid and stirred at ambient temperature overnight.Resulting4-(2-{[3-(tert-butyl)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH⁺=416.

[0248] Step 2. Synthesis of[4-(2-{[3-(tert-butyl)phenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamide

[0249] To4-(2-{[3-(tert-butyl)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid (1 eq) in tetrahydrofuran was added 2-piperidylethylamine (2 eq),HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambienttemperature for 16 h. The mixture was then concentrated and partitionedbetween ethyl acetate and water. The organic layer was concentrated andpreparative chromatography yielded[4-(2-{[3-(tert-butyl)phenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)-carboxamide.MS: MH⁺=512.

EXAMPLE 489 Synthesis of[4-(2-{[4-chloro-3-(trifluoromethyl)phenyl)amino-1-methyl-benzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamide

[0250] Step 1. Synthesis of4-{2-[(4-chloro-3-(trifluoromethyl)phenyl)amino]-1-methyl-benzimidazol-5-yloxy)pyridine-2-carboxylicacid

[0251] Totert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1eq) in methanol was added4-chloro-3-(trifluoromethyl)benzeneisothiocyanate (1 eq) and stir atambient temperature for 16 h. Formation of the corresponding thioureawas followed by LC/MS. To it was then added iodomethane (1 eq) andheated to 60° C. for 2 h. Formation oftert-butyl4-(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylatewas followed by LC/MS. To it in methylene chloride was addedtrifluoroacetic acid and stirred at ambient temperature overnight.Resulting4-(2-{[4-chloro-3-(trifluoromethyl)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH⁺=462.

[0252] Step 2. Synthesis of[4-(2-{[4-chloro-3-(trifluoromethyl)phenyl)amino-1-methyl-benzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamide

[0253] To4-(2-{[4-chloro-3-(trifluoromethyl)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid (1 eq) in tetrahydrofuran was added 2-piperidylethylamine (2 eq),HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambienttemperature for 16 h. The mixture was then concentrated and partitionedbetween ethyl acetate and water. The organic layer was concentrated andpreparative chromatography yielded[4-(2-{[4-chloro-3-trifluoromethylphenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamide.MS: MH⁺=558.

[0254] Each of the compounds 490-626 listed below in Table 6, weresynthesized as indicated in the right hand column by the methoddescribed in one of the Examples 482-489. TABLE 6 Synthesized as inExample Molecular Structure Name MH+ Example: 490

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-[(1-ethylpyrrolidin-2-yl)-methyl]pyridine-2-carboxamide 514.6 482 491

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-(2-morpholin-4-ylethyl)-pyridine-2-carboxamide 516.6 482 492

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-[3-(4-methylpiperazin-1-yl)propyl]pyridine-2-carboxamide 543.7 482 493

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-1,3-thiazol-2-ylpyridine- 2-carboxamide486.6 482 494

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-[2-(1-methylpyrrolidin-2-yl)ethyl]pyridine-2-carboxamide 514.6 482 495

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-(2-pyrrolidin-1-ylethyl)-pyridine-2-carboxamide 500.6 482 496

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-[3-(1H-imidazol-1-yl)-propyl]pyridine-2-carboxamide 511.6 482 497

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-[2-(methyloxy)ethyl]-pyridine-2-carboxamide 461.5 482 498

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-(2-hydroxyethyl)- pyridine-2-carboxamide447.5 482 499

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-(2-piperidin-1-ylethyl)-pyridine-2-carboxamide 514.6 482 500

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-(3-piperidin-1-ylpropyl)-pyridine-2-carboxamide 528.7 482 501

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-(3-pyrrolidin-1-ylpropyl)-pyridine-2-carboxamide 514.6 482 502

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-(2-pyridin-4-ylethyl)-pyridine-2-carboxamide 508.6 482 503

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-propylpyridine-2-carboxamide 445.5 482 504

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-(2-piperazin-1-ylethyl)-pyridine-2-carboxamide 515.6 482 505

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-[3-(methyloxy)propyl]-pyridine-2-carboxamide 475.6 482 506

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-ethylpyridine-2-carboxamide 431.5 482 507

N-[2-(acetylamino)ethyl]-4- [(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 488.6 482 508

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-[2-(2-oxoimidazolidin-1-yl)ethyl]pyridine-2-carboxamide 515.6 482 509

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-[(3R)-pyrrolidin-3-yl]-pyridine-2-carboxamide 472.6 482 510

4-[(2-{[4-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-[3-(2-oxopyrrolidin-1-yl)propyl]pyridine-2-carboxamide 528.6 482 511

4-({2-[(4-bromo-3- methylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(2- oxopyrrolidin-1- yl)propyl]pyridine-2-carboxamide 578.5483 512

4-[2-(acetylamino)ethyl]-4- ({2-[(4-bromo-3- methylphenyl)amino]-1-methyl-1H-benzimidazol-5- yl}oxy)pyridine-2-carboxamide 538.4 483 513

4-({2-[(4-bromo-3- methylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)- N-ethylpyridine-2-carboxamide 481.4483 514

4-({2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl- 1H-benzimidazol-5-yl}oxy)-N-(2-morpholin-4- ylethyl)pyridine-2-carboxamide 566.5 483 515

4-({2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2- (methyloxy)ethyl]pyridine-2-carboxamide511.4 483 516

4-({2-[(4-bromo-3- methylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(4- methylpiperazin-1-yl)propyl]pyridine-2-carboxamide 593.5 483 517

4-({2-[(4-bromo-3- methylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[(3R)-pyrrolidin- 3-yl]pyridine-2-carboxamide 522.4 483 518

4-({2-[(4-bromo-3- methylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(1-methyl- pyrrolidin-2-yl)ethyl]- pyridine-2-carboxamide564.5 483 519

4-({2-[(4-bromo-3- methylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(1H-imidazol- 1-yl)propyl]pyridine-2-carboxamide 561.5 483520

4-({2-[(4-bromo-3- methylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-1,3-thiazol-2-yl- pyridine-2-carboxamide 536.4 483 521

4-({2-[(4-bromo-3- methylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)- N-propylpyridine-2-carboxamide 495.4483 522

4-({2-[(4-bromo-3- methylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-pyrrolidin- 1-ylethyl)pyridine-2-carboxamide550.5 483 523

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-(2-hydroxyethyl)pyridine-2-carboxamide 490.4 484 524

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-[3-(2-oxopyrrolidin-1-yl)propyl]pyridine-2-carboxamide 571.5 484 525

4-[2-(acetylamino)ethyl]-4- [(2-{[2-fluoro-5-(trifluoromethyl)-phenyl]amino}-1-methyl-1H- benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 531.5 484 526

N-ethyl-4-[(2-{[2-fluoro-5- (trifluoromethyl)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 474.4 484 527

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-(2-morpholin-4-yl-ethyl)pyridine-2-carboxamide 559.5 484 528

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-[2-(methyloxy)ethyl]-pyridine-2-carboxamide 504.5 484 529

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-[3-(4-methylpiperazin-1-yl)propyl]pyridine-2-carboxamide 586.6 484 530

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-[2-(1-methylpyrrolidin-2-yl)ethyl]pyridine-2-carboxamide 557.6 484 531

4-[2-(dimethylamino)- ethyl]-4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}- 1-methyl-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 517.5 484 532

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- [3-(1H-imidazol-1-yl)-propyl]pyridine-2-carboxamide 554.5 484 533

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-1,3-thiazol-2-ylpyridine-2-carboxamide 529.5 484 534

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-(2-pyridin-4-ylethyl)-pyridine-2-carboxamide 551.5 484 535

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-propylpyridine-2- carboxamide488.5 484 536

4-[(2-{[2-fluoro-5-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-(2-pyrrolidin-1-ylethyl)-pyridine-2-carboxamide 543.5 484 537

4-({2-[(4-bromo-3- fluorophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[(1- ethylpyrrolidin-2-yl)methyl]pyridine-2-carboxamide 568.5485 538

4-({2-[(4-bromo-3- fluorophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(1-methyl- pyrrolidin-2-yl)ethyl]- pyridine-2-carboxamide568.5 485 539

4-({2-[(4-bromo-3- fluorophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[2- (methyloxy)ethyl]pyridine 2-carboxamide 515.4 485 540

4-({2-[(4-bromo-3- fluorophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-(2-piperidin-1- ylethyl)pyridine-2-carboxamide 568.5 485 541

4-({2-[(4-bromo-3- fluorophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-(2-pyridin-4- ylethyl)pyridine-2-carboxamide 562.4 485 542

4-({2-[(4-bromo-3- fluorophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(methyloxy)- propyl]pyridine-2-carboxamide 529.4 485 543

4-({2-[(4-bromo-3- fluorophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-propylpyridine- 2-carboxamide 499.4 485 544

4-({2-[(4-bromo-3- fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-ethylpyridine-2-carboxamide 485.3 485545

4-({2-[(4-bromo-3- fluorophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[(3R)-pyrrolidin- 3-yl]pyridine-2-carboxamide 526.4 485 546

4-({2-[(4-bromo-3- fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(2- oxopyrrolidin-1-yl)propyl]pyridine-2-carboxamide 582.4 485 547

N-[(1-ethylpyrrolidin-2- yl)methyl]-4-({1-methyl-2-[(4-methylphenyl)amino]- 1H-benzimidazol-5-yl}-oxy)pyridine-2-carboxamide 485.6 486 548

4-({1-methyl-2-[(4- methylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-(2-morpholin-4-ylethyl)pyridine- 2-carboxamide 487.6 486 549

4-({1-methyl-2-[(4- methylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-[3-(4-methylpiperazin-1- yl)propyl]pyridine-2-carboxamide 514.6 486 550

4-({1-methyl-2-[(4- methylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-1,3-thiazol-2-ylpyridine-2-carboxamide 457.5 486 551

4-({1-methyl-2-[(4- methylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-[2-(1-methylpyrrolidin-2- yl)ethyl]pyridine-2-carboxamide 485.6 486 552

4-({1-methyl-2-[(4- methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-(2-pyrrolidin-1- ylethyl)pyridine-2-carboxamide 471.6 486553

N-[2-(dimethylamino)- ethyl]-4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol- 5-yl}oxy)pyridine-2-carboxamide445.5 486 554

N-[3-(1H-imidazol-1- yl)propyl]-4-({1-methyl-2-[(4-methylphenyl)amino]-1H- benzimidazol-5-yl}oxy)pyridine-2-carboxamide 482.6 486 555

4-({1-methyl-2-[(4-methyl- phenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-[2-(methyloxy)ethyl]- pyridine-2-carboxamide 432.5 486 556

N-(2-hydroxyethyl)-4-({1- methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 418.5 486 557

4-({1-methyl-2-[(4- methylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-(2-piperidin-1-ylethyl)pyridine- 2-carboxamide 485.6 486 558

4-({1-methyl-2-[(4- methylphenyl)amino]-1H- benzimidazol-5-yl}oxy)-N-[3-(2-oxopyrrolidin-1-yl)propyl]pyridine-2-carboxamide 499.6 486 559

4-({1-methyl-2-[(4-methyl- phenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-(3-piperidin-1- ylpropyl)pyridine-2-carboxamide 499.6 486560

4-({1-methyl-2-[(4-methyl- phenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-(3-pyrrolidin-1- ylpropyl)pyridine-2-carboxamide 485.6 486561

4-({1-methyl-2-[(4- methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-(2-pyridin-4-yl- ethyl)pyridine-2-carboxamide 479.6 486 562

4-({1-methyl-2-[(4-methyl- phenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-(2-piperazin-1-yl- ethyl)pyridine-2-carboxamide 486.6 486563

4-({1-methyl-2-[(4- methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-[3-(methyloxy)- propyl]pyridine-2-carboxamide 446.5 486 564

4-({1-methyl-2-[(4- methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-propylpyridine-2- carboxamide 416.5 486 565

4-ethyl-4-({1-methyl-2-[(4- methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide 402.5 486 566

N-[2-(acetylamino)ethyl]-4- ({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 459.5 486 567

4-({1-methyl-2-[(4-methyl- phenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-[2-(2-oxoimidazolidin-1- yl)ethyl]pyridine-2-carboxamide486.5 486 568

4-({1-methyl-2-[(4- methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-[(3R)-pyrrolidin-3- yl]pyridine-2-carboxamide 443.5 486 569

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[(1-ethylpyrrolidin-2- yl)methyl]pyridine-2-carboxamide499.6 487 570

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-morpholin-4-ylethyl)- pyridine-2-carboxamide 501.6 487571

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(4-methylpiperazin-1- yl)propyl]pyridine-2-carboxamide528.7 487 572

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-1,3-thiazol-2-ylpyridine- 2-carboxamide 471.6 487 573

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(1-methylpyrrolidin-2- yl)ethyl]pyridine-2-carboxamide499.6 487 574

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-pyrrolidin-1-ylethyl)- pyridine-2-carboxamide 485.6 487575

N-[2-(dimethylamino)- ethyl]-4-({2-[(4-ethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}- oxy)pyridine-2-carboxamide 459.6 487 576

4-({2-[(4-ethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(1H-imidazol-1-yl)-propyl]pyridine-2-carboxamide 496.6 487 577

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(methyloxy)ethyl]- pyridine-2-carboxamide 446.5 487 578

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-hydroxyethyl)pyridine- 2-carboxamide 432.5 487 579

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-piperidin-1-ylethyl)- pyridine-2-carboxamide 499.6 487580

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(3-piperidin-1-ylpropyl)- pyridine-2-carboxamide 513.7 487581

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(3-pyrrolidin-1-yl- propyl)pyridine-2-carboxamide 499.6 487582

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-pyridin-4-ylethyl)- pyridine-2-carboxamide 493.6 487 583

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-piperazin-1-ylethyl)- pyridine-2-carboxamide 500.6 487584

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(methyloxy)propyl]- pyridine-2-carboxamide 460.5 487 585

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-propylpyridine-2-carboxamide 430.5 487 586

N-ethyl-4-({2-[(4-ethyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridine- 2-carboxamide 416.5 487 587

N-[2-(acetylamino)ethyl]-4- ({2-[(4-ethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide 473.5 487 588

4-({2-[(4-ethylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(2-oxoimidazolidin-1- yl)ethyl]pyridine-2-carboxamide500.6 487 589

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[(1-ethyl- pyrrolidin-2-yl)methyl]-pyridine-2-carboxamide 527.7 488 590

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-morpholin- 4-ylethyl)pyridine-2-carboxamide529.7 488 591

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(4- methylpiperazin-1-yl)propyl]pyridine-2-carboxamide 556.7 488 592

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-1,3-thiazol- 2-yl-pyridine-2-carboxamide 499.6488 593

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(1-methyl- pyrrolidin-2-yl)ethyl]-pyridine-2-carboxamide 527.7 488 594

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-pyrrolidin- 1-ylethyl)pyridine-2-carboxamide513.7 488 595

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(1H- imidazol-1-yl)propyl]pyridine-2-carboxamide 524.6 488 596

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2- (methyloxy)ethyl]pyridine-2-carboxamide474.6 488 597

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2- hydroxyethyl)pyridine-2-carboxamide 460.5488 598

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-piperidin- 1-yl-ethyl)pyridine-2-carboxamide527.7 488 599

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(2- oxopyrrolidin-1-yl)propyl]pyridine-2-carboxamide 541.7 488 600

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(3-piperidin-1-yl-propyl)pyridine-2-carboxamide 541.7 488 601

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(3-pyrrolidin-1-ylpropyl)pyridine-2-carboxamide 527.7 488 602

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-pyridin-4- ylethyl)pyridine-2-carboxamide521.6 488 603

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-piperazin-1- ylethyl)pyridine-2-carboxamide528.7 488 604

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(methyloxy)- propyl]pyridine-2-carboxamide488.6 488 605

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-propylpyridine- 2-carboxamide 458.6 488 606

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-ethylpyridine- 2-carboxamide 444.5 488 607

N-[2-(acetylamino)ethyl]-4- [(2-{[3-(1,1-dimethylethyl)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-pyridine-2-carboxamide 501.6488 608

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(2-oxo- imidazolidin-1-yl)ethyl]-pyridine-2-carboxamide 528.6 488 609

4-[(2-{[3-(1,1-dimethyl- ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[(3R)- pyrrolidin-3-yl]pyridine-2-carboxamide485.6 489 610

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-[2-(1-methylpyrrolidin-2-yl)ethyl]pyridine-2-carboxamide 574.0 489 611

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-[3-(1H-imidazol-1-yl)propyl]pyridine-2-carboxamide 571.0 489 612

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-[2-(dimethylamino)-ethyl]pyridine-2-carboxamide 534.0 489 613

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-[3-(methyloxy)propyl]-pyridine-2-carboxamide 534.9 489 614

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-propylpyridine-2-carboxamide 504.9489 615

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-ethylpyridine-2-carboxamide 490.9489 616

4-[2-(acetylamino)ethyl]-4- [(2-{[4-chloro-3-(trifluoromethyl)-phenyl]amino}-1-methyl-1H- benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 547.9 489 617

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-(2-morpholin-4-yl-ethyl)pyridine-2-carboxamide 576.0 489 618

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-[3-(4-methylpiperazin-1-yl)propyl]pyridine-2-carboxamide 603.1 489 619

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-(2-pyrrolidin-1-ylethyl)pyridine-2-carboxamide 560.0 489 620

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-[2-(methyloxy)ethyl]-pyridine-2-carboxamide 520.9 489 621

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-(2-piperidin-1-ylethyl)-pyridine-2-carboxamide 574.0 489 622

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- (3-piperidin-1-yl-propyl)pyridine-2-carboxamide 588.0 489 623

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-(2-pyridin-4-ylethyl)-pyridine-2-carboxamide 568.0 489 624

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-(2-piperazin-1-ylethyl)-pyridine-2-carboxamide 575.0 489 625

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-[(3R)-pyrrolidin-3-yl]-pyridine-2-carboxamide 531.9 489 626

4-[(2-{[4-chloro-3-(tri- fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-[3-(2-oxopyrrolidin-1-yl)propyl]pyridine-2-carboxamide 588.0 489

EXAMPLE 627

[0255] Step 1. Synthesis of[4-(2-{[4-(chloromethyl)phenyl]carbonylamino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide

[0256] A solution of sodium thiocyanate (1 eq) in acetone was addedslowly in to a solution of 4-(chloromethyl)benzoylchloride (1 eq) inacetone at 0° C. The mixture was then filtered in to a solution of{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1eq) in acetone. Formation of N-acylthiourea was followed by LC/MS. Themixture was concentrated and taken in tetrahydrofuran and to it wasadded 1-ethyl-(3-dimethylaminopropyl)carbodiimidehydrochloride (2 eq)and stirred at ambient temperature for 16 h. The mixture wasconcentrated and partitioned between ethyl acetate and water. Theorganic layer was then dried and concentrated to yield[4-(2-{[4-(chloromethyl)phenyl]carbonylamino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide.MS: MH⁺=449.

[0257] Step 2. Synthesis ofN-methyl{4-[1-methyl-2-({4-[(4methylpiperazinyl)methyl]phenyl}carbonylamino)benzimidazol-5-yloxy](2-pyridyl)}carboxamide.

[0258] To a solution of[4-(2-{[4-(chloromethyl)phenyl]carbonylamino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide(1 eq) in tetrahydrofuran was added methylpiperazine (4 eq) and stirredat ambient temperature for 16 h. The reaction mixture was concentratedand purified on preparative chromatography to yieldN-methyl{4-[1-methyl-2-({4-[(4methylpiperazinyl) methyl]phenyl}carbonylamino) benzimidazol-5-yloxy](2-pyridyl)}carboxamide. MS:MH⁺=512.

EXAMPLE 628

[0259] Step 1. Synthesis ofN-methyl[4-(1-methyl-2-{2-{4-[(4-methylpiperazinyl)-methylphenyl}-benzimidazol-5-yloxy)(2-pyridyl)]carboxamide

[0260] To a solution of{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1eq) in tetrahydrofuran was added 4-(chloromethyl)benzoylchloride (1 eq)and triethylamine (2 eq). N-acylation is completed in 0.5 h. Thereaction mixture was concentrated and partitioned between ethyl acetateand water. The organic layer was concentrated and to the crude productwas added methylpiperazine (4 eq) and tetrahydrofuran and stir for 16 hat ambient temperature. The reaction mixture was concentrated andpartitioned between ethyl acetate and water. The organic layer wasconcentrated and taken in acetic acid and heated to 60° C. for 3 h.Preparative chromatography yieldedN-methyl[4-(1-methyl-2-{2-{4-[(4-methylpiperazinyl)methyl-phenyl}-benzimidazol-5-yloxy)(2-pyridyl)]carboxamide.MS: MH⁺=470.

EXAMPLE 629

[0261] Step 1. Synthesis of 2-chloro-4-(3-pyridyl)pyrimidine

[0262] Nitrogen was bubbled through a solution of 2,4-dichloropyrimidine(1 eq) in tetrahydrofuran and water (3:1) for 0.5 h.Bis(diphenylphosphino)ferrocene Palladium(II)chloride (0.05 eq) followedby pyridine-3-boronic acid (1 eq) and sodium carbonate (3 eq) was addedand the mixture was heated to 60° C. for 16 h under nitrogen. Thereaction mixture was concentrated and partitioned between ethyl acetateand water. The organic layer was washed with brine and dried with sodiumsulfate and concentrated. Purification on silica gel gave2-chloro-4-(3-pyridyl)pyrimidine. MS: MH⁺=190.

[0263] Step 2. Synthesis of2-nitro-4-(4-(3-pyridyl)pyrimidin-2-yloxy)phenylamine

[0264] A solution of 4-amino-3-nitro-phenol (1 eq) and2-chloro-4-(3-pyridyl)pyrimidine (1 eq) in N,N-dimethylformamide wasmicrowaved at 150° C. for 10 mins. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was concentrated andpurified on silica gel to yield2-nitro-4-(4-(3-pyridyl)pyrimidin-2-yloxy)phenylamine. MS: MH⁺=309.

[0265] Step 3. Synthesis of4-(4-(3-pyridyl)pyrimidin-2-yloxy)benzene-1,2-diamine

[0266] The mixture containing2-nitro-4-(4-(3-pyridyl)pyrimidin-2-yloxy)phenylamine in methanol withcatalytic amount of 10% Pd/C was hydrogenated until disappearance ofyellow color to yield4-(4-(3-pyridyl)pyrimidin-2-yloxy)benzene-1,2-diamine. MS: MH⁺=279.

[0267] Step 3. Synthesis of{4-[(4-methylpiperazinyl)methyl]phenyl}-N-[5-(4-(3-pyridyl)pyrimidin-2-yloxy)benzimidazol-2-yl]carboxamide.

[0268] A solution of sodium thiocyanate (1 eq) in acetone was addedslowly in to a solution of 4-(chloromethyl)benzoylchloride (1 eq) inacetone at 0° C. The mixture was then filtered in to a solution of4-(4-(3-pyridyl)pyrimidin-2-yloxy)benzene-1,2-diamine (1 eq) in acetone.Formation of N-acylthiourea was followed by LC/MS. The mixture wasconcentrated and taken in tetrahydrofuran and to it was added1-ethyl-(3-dimethylaminopropyl)carbodiimidehydrochloride (2 eq) andstirred at ambient temperature for 16 h. The mixture was concentratedand partitioned between ethyl acetate and water. The organic layer wasthen dried and concentrated to yield[4-(chloromethyl)phenyl]-N-[5-(4-(3-pyridyl)pyrimidin-2-yloxy)benzimidazol-2-yl]carboxamide.It was taken in tetrahydrofuran and added methylpiperazine (4 eq) andstirred at ambient temperature for 16 h. The reaction mixture wasconcentrated and purified on preparative chromatography to yield{4-[(4-methylpiperazinyl)methyl]phenyl}-N-[5-(4-(3-pyridyl)pyrimidin-2-yloxy)benzimidazol-2-yl]carboxamide.MS: MH⁺=520.

EXAMPLE 630

[0269] Step 1. Synthesis of 4-ethyl-1-[(4-nitrophenyl)methylpiperazine

[0270] To 4-(chloromethyl)-1-nitrobenzene(1 eq) in tetrahydrofuran wasadded Ethylpiperazine (3 eq) and stir for 16 h at ambient temperature.Concentrating and passing through a plug of silica gave4-ethyl-1-[(4-nitrophenyl)methylpiperazine. MS: MH⁺=249

[0271] Step 2. Synthesis of 4-[(4-ethylpiperazinyl)methyl]phenylamine

[0272] The mixture containing 4-ethyl-1-[(nitrophenyl)methylpiperazinein methanol with catalytic amount of 10% Pd/C was hydrogenated to yield4-[(4-ethyl-piperazinyl)methyl]phenylamine. MS: MH⁺=219.

[0273] Step 3. Synthesis of4-[(4-ethylpiperazinyl)methyl]benzeneisothiocyanate

[0274] To 4-[(4-ethylpiperazinyl)methyl]phenylamine in acetone at 0° C.was added sodium bicarbonate (2 eq) and thiophosgene (2 eq). The mixturewas brought to ambient temperature and concentrated and partitionedbetween ethyl acetate and water. The organic layer was dried with sodiumbicarbonate and sodium sulfate and concentrated to yield4-[(4-ethylpiperazinyl)methyl]benzeneisothiocyanate. MS: MH⁺=261.

[0275] Step 4. Synthesis of[4-[(2-{[4-ethylpiperazinyl)methyl]phenyl]amino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide

[0276] To 4-[(4-ethylpiperazinyl)methyl]benzeneisothiocyanate(1 eq) inmethanol was added{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1eq) and heated to 60° C. for 16 h. Preparative chromatography yielded[4-[(2-{[4-ethylpiperazinyl)methyl]phenyl]amino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide.MS: MH⁺=499.

EXAMPLE 631

[0277] Step 1. Synthesis of 4-Ethyl-1-(4-nitrophenyl)piperazine

[0278] To 4-fluoro-1-nitrobenzene(1 eq) in N,N-dimethylformamide wasadded Ethyl piperazine (2 eq) and N,N-diisopropylethyl amine (2 eq) andheated at 80° C. for 16 h. Concentrated the resultant mixture andpartitioned between ethyl acetate and water. The organic layer was thenwashed with brine and dried with sodium sulfate and concentrated. Passedthrough a plug of silica to yield 4-Ethyl-1-(4-nitrophenyl)piperazine.MS: MH⁺=235.

[0279] Step 2. Synthesis of 4-(4-ethylpiperazinyl)phenylamine

[0280] The mixture containing 4-ethyl-1-(4-nitrophenyl)piperazine inmethanol with catalytic amount of 10% Pd/C was hydrogenated to yield4-(4-ethylpiperazinyl)phenyl-amine. MS: MH⁺=205.

[0281] Step 3. Synthesis of 4-(4-ethylpiperazinyl)benzeneisothiocyanate

[0282] To 4-(4-ethylpiperazinyl)phenylamine in acetone at 0° C. wasadded sodium bicarbonate (2 eq) and thiophosgene (2 eq). The mixture wasbrought to ambient temperature and concentrated and partitioned betweenethyl acetate and water. The organic layer was dried with sodiumbicarbonate and sodium sulfate and concentrated to yield4-(4-ethylpiperazinyl)benzeneisothiocyanate. MS: MH⁺=247.

[0283] Step 3. Synthesis of[4-(2-{[4-ethylpiperazinyl)phenyl]amino)-1-methyl-benzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide

[0284] To 4-(4-ethylpiperazinyl)benzeneisothiocyanate (1 eq) in methanolwas added{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1eq) and heated to 60° C. for 16 h. Preparative purification yielded[4-(2-{[4-ethylpiperazinyl)phenyl]-amino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide.MS: MH⁺=485.

EXAMPLE 632

[0285] Step 1. Synthesis of 4-[2-(4-nitrophenyl)ethylmorpholine

[0286] To 4-(2-bromoethyl)-1-nitrobenzene(1 eq) in tetrahydrofuran wasadded morpholine (3 eq) and stir for 16 h at ambient temperature.Concentrating and passing through a plug of silica gave4-[2-(4-nitrophenyl)ethylmorpholine. MS: MH⁺=236.

[0287] Step 2. Synthesis of 4-(2-morpholin-4-ylethyl)phenylamine

[0288] The mixture containing 4-[2-(4-nitrophenyl)ethyl]morpholine inmethanol with catalytic amount of 10% Pd/C was hydrogenated to yield4-(2-morpholin-4-ylethyl)phenylamine. MS: MH⁺=206.

[0289] Step 3. Synthesis of4-(2-morpholin-4-ylethyl)benzeneisothiocyanate

[0290] To 4-(2-morpholin-4-ylethyl)phenylamine in acetone at 0° C. wasadded sodium bicarbonate (2 eq) and thiophosgene (2 eq). The mixture wasbrought to ambient temperature and concentrated and partitioned betweenethyl acetate and water. The organic layer was dried with sodiumbicarbonate and sodium sulfate and concentrated to yield4(2-morpholin-4-ylethyl)benzeneisothiocyanate. MS: MH⁺=252.

[0291] Step 4. Synthesis ofN-methyl[4-(1-methyl-2-{[4-(2-morpholin-4-ylethyl)phenyl]amino}-benzimidazol-5-oxy)(2-pyridyl)]carboxamide

[0292] To 4(2-morpholin-4-ylethyl)benzeneisothiocyanate (1 eq) inmethanol was added{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1eq) and stirred at ambient temperature for 16 h. The correspondingthiourea formation was followed by LC/MS. To it was the addediodomethane(1 eq) and heated to 60° C. for 3 h. Concentration followedby preparative chromatography yieldedN-methyl[4-(1-methyl-2-{[4-(2-morpholin-4-ylethyl)phenyl]amino}-benzimidazol-5-oxy)(2-pyridyl)]carboxamide.MS: MH⁺=486.

EXAMPLE 633

[0293] Step 1. Synthesis of [(4-nitrophenyl)ethyl]benzylamine

[0294] To a solution of 1-(4-nitrophenyl)ethan-1-one (1 eq) andphenylmethylamine (1 eq) in methanol was added sodiumtriacetoxyborohydride (1.2 eq). The resulting mixture was stirred atambient temperature for 16 h. The mixture was concentrated andpartitioned between ethyl acetate and water. The organic layer wasconcentrated and preparative purification yielded [(4-nitrophenyl)ethyl]benzylamine. MS: MH⁺=256.

[0295] Step 2. Synthesis of [(4-aminophenyl)ethyl]benzylamine

[0296] The mixture containing [(4-nitrophenyl) ethyl]benzylamine inmethanol with catalytic amount of 10% Pd/C was hydrogenated untildisappearance of yellow color to yield[(4-aminophenyl)ethyl]benzylamine. MS: MH⁺=226.

[0297] Step 3. Synthesis of 4-{[benzylamino]ethyl}benzeneisothiocyanate

[0298] To [(4-nitrophenyl) ethyl]benzylamine in acetone at 0° C. wasadded sodium bicarbonate (2 eq) and thiophosgene (2 eq). The mixture wasbrought to ambient temperature and concentrated and partitioned betweenethyl acetate and water. The organic layer was dried with sodiumbicarbonate and sodium sulfate and concentrated toyield4-{[benzylamino]ethyl}benzeneisothiocyanate. MS: MH⁺=268.

[0299] Step 4. Synthesis ofN-methyl(4-{1-methyl-2-2[(4-{[benzylamino]ethyl}-phenyl)amino)benzimidazol-5-yloxy)-(2-pyridyl))carboxamide

[0300] To a solution of[4-(3,4-diaminophenoxy)(2-pyridyl))]-N-methylcarboxamide(1 eq) inmethanol was added 4-{[benzylamino]ethyl}benzeneisothiocyanate (1 eq)and heated to 60° C. for 3 h. Preparative chromatography yieldedN-methyl(4-{1-methyl-2-2-[(4-{[benzylamino] ethyl}phenyl)amino)benzimidazol-5-yloxy)-(2-pyridyl))-carboxamide. MS: MH⁺=506.

EXAMPLE 634

[0301] Step 1. Synthesis of (5-fluoro-2-nitrophenyl)methylamine

[0302] A solution of 5-fluoro-2-nitrophenylamine (1 eq) inmethylenechloride was treated with trifluoroacetic anhydride (1 eq) andstirred for 10 minutes at 0° C. The mixture was quenched with saturatedsodium bicarbonate solution. The organic layer was separated and washedwith water, brine, dried and evaporated. To the solution of thetrifluoroacetamide (1 eq) in a mixture of toluene, acetonitrile andsodium hydroxide solution (50%) was added benzyltrimethylammoniumchloride (1 eq) and dimethyl sulfate (1.2 eq). The biphasic mixture wasstirred overnight at room temperature and evaporated. The mixture wastaken up in ethyl acetate, washed with water, brine, dried andevaporated. The crude was purified by column chromatography eluting with1:1 hexanes and ethyl acetate to afford(5-fluoro-2-nitrophenyl)methylamine. MS: MH⁺=170.

[0303] Step 2. Synthesis of{4-[4-amino-3-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide

[0304] The mixture containing 5-fluoro-2-nitrophenylamine (1 eq),Potassium bis(trimethylsilyl)amide (2 eq) was stirred indimethylformamide for 2 hours at room temperature. To this mixture wasadded (3-hydroxyphenyl)-N-methylcarboxamide (1 eq) and Potassiumcarbonate (1.2 eq) and stirred at 90° C. for 16 h. The reaction mixturewas then concentrated and partitioned between ethyl acetate and water.The organic layer was separated and washed with brine, dried, filteredand concentrated in vacuum to give brown solid. Purification on silicagel gaveN-methyl{4-[3-(methylamino)-4-nitro-phenoxy](2-pyridyl))carboxamide. Itwas taken in methanol and hydrogenated with catalytic amount of 10% Pd/Cto give{4-[4-amino-3-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide. MS:MH⁺=272.

[0305] Step 3. Synthesis of(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-6-yloxy)-(2-pyridyl)-N-methylcarboxamide

[0306] A solution of the{4-[4-amino-3-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide(1eq) in methanol was treated with 4-bromophenylisothiocyanate (1 eq) andstirred at 60° C. for 2 hours. The reaction mixture was cooled down toroom temperature and iodomethane (1 eq) was added and stirred overnightat 60° C. The reaction was concentrated and preparative chromatographygave(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-6-yloxy)-(2-pyridyl)-N-methylcarboxamide.MS: MH⁺=452.

EXAMPLE 635

[0307] Step 1. Synthesis of((5-aminobenzimidazol-2-yl)(4-bromophenylamine)

[0308] A solution of the 4-nitrobenzene-1,2-diamine in methanol wastreated with 4-bromo phenyl isothiocyanate (1 eq) and stirred at 60° C.for 2 hours. The reaction mixture was cooled down to room temperatureand iodomethane (1 eq) was added and stirred overnight at 60° C. Thereaction was concentrated and purified on silica gel to yield(4-bromophenyl)(5-nitrobenzimidazol-2-yl)amine. The product was taken inmethanol and hydrogenated with catalytic amount of 10% Pd/C to give((5-aminobenzimidazol-2-yl)(4-bromophenylamine). MS: MH⁺=302.

[0309] Step 2. Synthesis of[4-({2-[(4-bromophenyl)amino}benzimidazol-5-yl}amino)-(2-pyridyl_-N-methylcarboxamide

[0310] To a solution of ((5-aminobenzimidazol-2-yl)(4-bromophenylamine(1eq) in N,N-dimethylformamide was added sodium hydride (2 eq) and themixture was microwaved for 8 mins at 220° C. The reaction mixture waspartitioned between ethyl acetate and water and the organic layer wasdried with sodium sulfate and concentrated. Preparative chromatographyyielded[4-({2-[(4-bromophenyl)amino}benzimidazol-5-yl}amino)(2-pyridyl_-N-methylcarboxamide.MS: MH⁺=437.

EXAMPLE 636

[0311] Step 1. Synthesis of(4-{2-[(4-bromophenyl)methyl]-1-methylbenzimidazol-5-yloxy)-(2-pyridyl))-N-methylcarboxamide

[0312] To 4-bromophenyl acetic acid (1 eq) in dichoromethane containinga drop of N,N-dimethyl formamide at 0° C. was added oxalyl chloride (1.2eq). The resulting mixture was then brought to ambient temperature andstirred for 2 h. The mixture was concentrated and to it was addedtetrahydrofuran and[4-(3,4-diaminophenoxy)(2-pyridyl)]-N-methylcarboxamide (1 eq) andtriethyl amine (1 eq) and stirred for 2 h. Formation of the N-acylatedproduct was followed by LC/MS. The mixture was concentrated andpartitioned between ethyl acetate and water. The organic layer was driedwith sodium sulfate and concentrated and taken in acetic acid and heatedto 60° C. for 2 h. Preparative chromatography yielded(4-{2-[(4-bromophenyl)methyl]-1-methylbenzimidazol-5-yloxy)-(2-pyridyl))-N-methylcarboxamide.MS: MH⁺=451.

EXAMPLE 637

[0313] Step 1. Synthesis of4-({1-methyl-5-[2-(N-methylcarbamoyl)(4-pyridyl-oxy))]benzimidazol-2-yl}amino)benzoicacid

[0314] To{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1eq) in methanol was added 4-isothiocyanatobenzoic acid (1 eq) andstirred at 60° C. for 3 h. To it was then added iodomethane (1 eq) andheated to 60° C. for 3 h. and concentrated the solvent and purified onsilica gel to yield4-({1-methyl-5-[2-(N-methylcarbamoyl)(4-pyridyloxy))]benzimidazol-2-yl}amino)benzoicacid. MS: MH⁺=417.

[0315] Step 2. Synthesis ofN-methyl[4-(1-methyl-2-{[4-(2-morpholin-4-ylethyl)phenyl]-amino-benzimidazol-5-oxy)(2-pyridyl)]carboxamideCHIR-164277

[0316] To4-({1-methyl-5-[2-(N-methylcarbamoyl)(4-pyridyloxy))]benzimidazol-2-yl}-amino)benzoicacid (1 eq) in tetrahydrofuran was added morpholine (2 eq) andN,N-diisopropylethylamine (4 eq) and HBTU(2 eq) and stir at ambienttemperature for 16 h. The mixture was then concentrated and partitionedbetween ethyl acetate and water. The organic layer was washed with brineand dried with sodium sulfate. Preparative chromatography gaveN-methyl[4-(1-methyl-2-{[4-(2-morpholin-4-ylethyl)phenyl]-amino-benzimidazol-5-oxy)(2-pyridyl)]carboxamide.MS: MH⁺=529.

EXAMPLE 638

[0317] Step 1. Synthesis of3-({1-methyl-5-[2-(N-methylcarbamoyl)(4-pyridyloxy))]benzimidazol-2-yl}amino)benzoic acid

[0318] To 4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1 eq) in methanol was added3-isothiocyanatobenzoic acid (1 eq) and stirred at 60° C. for 3 h. To itwas then added iodomethane (1 eq) and heated to 60° C. for 3 h andconcentrated the solvent and purified on silica gel to yield3-({1-methyl-5-[2-(N-methylcarbamoyl)(4-pyridyloxy))] benzimidazol-2-yl}amino)benzoic acid. MS: MH⁺=417.

[0319] Step 2. Synthesis ofN-methyl[3-(1-methyl-2-{[4-(2-morpholin-4-ylethyl)phenyl]-amino-benzimidazol-5-oxy)(2-pyridyl)]carboxamide

[0320] To3-({1-methyl-5-[2-(N-methylcarbamoyl)(4-pyridyloxy))]benzimidazol-2-yl}-amino)benzoicacid (1 eq) in tetrahydrofuran was added morpholine (2 eq) andN,N-diisopropylethylamine (4 eq), EDCI (2 eq), HOAT(1.2 eq) and stir atambient temperature for 16 h. The mixture was then concentrated andpartitioned between ethyl acetate and water. The organic layer waswashed with brine and dried with sodium sulfate. Preparativechromatography gaveN-methyl[3-(1-methyl-2-{[4-(2-morpholin-4-ylethyl)-phenyl]amino-benzimidazol-5-oxy)(2-pyridyl)]carboxamide.MS: MH⁺=529.

[0321] Each of the compounds 639-698, listed in Table 7 were synthesizedas indicated in the right hand column by the method described in one ofthe Examples 627-638 or as otherwise indicated. TABLE 7 Synthesis as inExample Structure Name MH+ Example: 639

4-({2-[(4-bromophenyl)- methyl]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 452.3 636 640

4-({2-[(4-bromophenyl)- amino]-1H-benzimidazol-6-yl}amino)-N-methylpyridine- 2-carboxamide 438.3 635 641

4-({2-[(4-bromophenyl)- amino]-1-methyl-1H- benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide 453.3 634 642

N-methyl-4-({1-methyl-2- [(4-{1-[(phenylmethyl)-amino]ethyl}phenyl)amino]- 1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide 507.6 633 643

4-({2-[(4-{[2-(dimethyl- amino)ethyl]oxy}phenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 461.5 631 644

N-methyl-4-{[1-methyl-2- ({4-[(methylamino)- carbonyl]phenyl}amino)-1H-benzimidazol-5-yl]oxy}- pyridine-2-carboxamide 431.5 637 645

N-methyl-4-({1-methyl-2- [(4-{[(2-morpholin-4-yl- ethyl)amino]carbonyl}-phenyl)amino]-1H- benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 530.6637 646

4-{[2-({4-[(4-ethylpiperazin- 1-yl)carbonyl]phenyl}- amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N- methylpyridine-2-carboxamide 514.6 637 647

N-methyl-4-({1-methyl-2- [(4-{[(2-pyridin-4-ylethyl)-amino]carbonyl}phenyl)amino]- 1H-benzimidazol-5-yl}-oxy)pyridine-2-carboxamide 522.6 637 648

4-[(2-{[4-({[2-(dimethyl- amino)ethyl]amino}- carbonyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-methylpyridine-2- carboxamide 488.6637 649

4-({2-[(4-{[3-(dimethyl- amino)pyrrolidin-1-yl]-carbonyl}phenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 514.6 637 650

N-methyl-4-({1-methyl-2- [(4-{[(1-methylethyl)amino]-carbonyl}phenyl)amino]-1H- benzimidazol-5-yl}oxy)-pyridine-2-carboxamide 459.5 637 651

4-[(2-{[4-(2,6-dimethyl- morpholin-4-yl)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl) oxy]-N-methylpyridine-2-carboxamide 487.6120a 652

4-methyl-4-({1-methyl-2- [(4-piperidin-1-ylphenyl)-amino]-1H-benzimidazol-5- yl}oxy)pyridine-2-carboxamide 457.5 120a 653

4-methyl-4-[(1-methyl-2- {[4-({[2-(1-methylpyrrolidin-2-yl)ethyl]amino}carbonyl)- phenyl]amino}-1H- benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 528.6 637 654

N-methyl-4-({1-methyl-2- [(4-{[(2-piperidin-1-ylethyl)-amino]carbonyl}phenyl)amino]- 1H-benzimidazol-5-yl}-oxy)pyridine-2-carboxamide 528.6 637 655

4-[(2-{[4-({[3-(1H-imidazol- 1-yl)propyl]amino}carbonyl)-phenyl]amino}-1-methyl-1H- benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide 525.6 637 656

4-[(2-{[4-({[(1-ethyl- pyrrolidin-2-yl)methyl]- amino}carbonyl)phenyl]-amino}-1-methyl-1H- benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide 528.6 637 657

N-methyl-4-({1-methyl-2- [(4-{[(2-pyrrolidin-1-yl-ethyl)amino]carbonyl}- phenyl)amino]-1H- benzimidazol-5-yl}oxy)-pyridine-2-carboxamide 514.6 637 658

N-methyl-4-({1-methyl-2- [(4-{[(pyridin-4-ylmethyl)-amino]carbonyl}phenyl)- amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide 508.6 637 659

N-methyl-4-{[1-methyl-2- ({4-[(1,3-thiazol-2-yl-amino)carbonyl]phenyl}amino)- 1H-benzimidazol-5-yl]-oxy}pyridine-2-carboxamide 500.6 637 660

N-methyl-4-[(1-methyl-2- {[4-({[3-(4-methylpiperazin-1-yl)propyl]amino}carbonyl)- phenyl]amino}-1H- benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 557.7 637 661

4-{[2-({4-[(1-aza- bicyclo[2.2.2]oct-3-ylamino)-carbonyl]phenyl}amino)-1- methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide 526.6 637 662

4-({2-[(4-{[(3S)-1- azabicyclo[2.2.2]oct-3-ylamino]carbonyl}phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 526.6637 663

N-methyl-4-{[1-methyl-2- ({4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amino)- 1H-benzimidazol-5-yl]oxy}-pyridine-2-carboxamide 500.6 637 664

N-methyl-4-{[1-methyl-2- ({4-[(4-methyl-1,4-diazepan-1-yl)carbonyl]phenyl}- amino)-1H-benzimidazol-5-yl]oxy}pyridine-2-carboxamide 514.6 637 665

N-methyl-4-[(1-methyl-2- {[4-({[3-(2-oxopyrrolidin-1-yl)propyl]amino}carbonyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 542.6 637 666

4-({2-[(4-{[(3R)-3-hydroxy- pyrrolidin-1-yl]carbonyl}-phenyl)amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 487.5 637 667

4-({2-[(4-{[(3S)-3-hydroxy- pyrrolidin-1-yl]carbonyl}-phenyl)amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 487.5 637 668

4-({2-[(4-{[4-(2-hydroxy- ethyl)piperazin-1-yl]-carbonyl}phenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 530.6 637 669

4-{[2-({4-[(4-acetylpiperazin- 1-yl)carbonyl]phenyl}-amino)-1-methyl-1H- benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide 528.6 637 670

4-({2-[(4-{[(3R)-3-(dimethyl- amino)pyrrolidin-1-yl]-carbonyl}phenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 514.6 637 671

4-({2-[(4-{[(3S)-3-(dimethyl- amino)pyrrolidin-1-yl]-carbonyl}phenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 514.6 637 672

N-methyl-4-({1-methyl-2- [(4-{[(tetrahydrofuran-2-ylmethyl)amino]carbonyl}- phenyl)amino]-1H- benzimidazol-5-yl}oxy)-pyridine-2-carboxamide 501.6 637 673

4-({2-[(4-{[(3R)-3-(acetyl- amino)pyrrolidin-1-yl]-carbonyl}phenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 528.6 637 674

4-[(2-{[4-(1,4′-bipiperidin-1′- ylcarbonyl)phenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-methylpyridine-2-carboxamide 568.7637 675

N-methyl-4-[(1-methyl-2- {[4-(morpholin-4-yl- carbonyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 487.5 637 676

4-({2-[(4-{[(3R,5S)-3,5- dimethylpiperazin-1-yl]-carbonyl}phenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 514.6 637 677

N-methyl-4-[(1-methyl-2- {[4-(pyrrolidin-1-yl-carbonyl)phenyl]amino}-1H- benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 471.5 637 678

4-({2-[(4-{[(2R)-2-(amino- carbonyl)pyrrolidin-1-yl]-carbonyl}phenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide 514.6 637 679

N-methyl-4-({1-methyl-2- [(4-{[4-(1-methylethyl)-piperazin-1-yl]carbonyl}- phenyl)amino]-1H- benzimidazol-5-yl}oxy)-pyridine-2-carboxamide 528.6 637 680

4-[(2-{[4-({(2R,5S)-2- [(dimethylamino)methyl]-5- methylmorpholin-4-yl}-carbonyl)phenyl]amino}-1- methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide 558.7 637 681

N-methyl-4-({1-methyl-2- [(4-{[(1-methylpiperidin-4-yl)amino]carbonyl}phenyl) amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide 514.6 637 682

4-[(2-{[4-({2- [(dimethylamino)methyl]morpholin-4-yl}carbonyl)-phenyl]amino}-1-methyl-1H- benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide 544.6 637 683

4-{[2-({4-[(4-ethylpiperazin- 1-yl)methyl]phenyl}amino)-1-methyl-1H-benzimidazol-5- yl]oxy}-N-methylpyridine-2-carboxamide 500.6630 684

N-methyl-4-{[1-methyl-2- ({4-[methyl(1-methyl- pyrrolidin-3-yl)amino]-phenyl}amino)-1H- benzimidazol-5-yl]oxy}- pyridine-2-carboxamide 486.6631 685

4-{[2-({4-[[2-(dimethyl- amino)ethyl](methyl)amino]-phenyl}amino)-1-methyl-1H- benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide 474.6 631 686

4-[(2-{[4-(4-ethylpiperazin-1- yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-methylpyridine-2-carboxamide 486.6 631 687

4-{[2-({4-[2-(4- ethylpiperazin-1-yl)ethyl]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}- N-methylpyridine-2-carboxamide 514.6 632 688

N-methyl-4-[(1-methyl-2- {[4-(2-morpholin-4- ylethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide 487.6 632 689

N-methyl-4-[(1-methyl-2- {[4-(2-piperidin-1- ylethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 485.6 632 690

N-methyl-4-[(1-methyl-2-{4- [(4-methylpiperazin-1- yl)methyl]phenyl}-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 471.6 628 691

N-methyl-4-({1-methyl-2- [({4-[(4-methylpiperazin-1-yl)methyl]phenyl}carbonyl) amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide 514.6 627 692

N-methyl-4-{[1-methyl-2- ({[4-(morpholin-4-ylmethyl)phenyl]carbonyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2-carboxamide 501.6 627 693

N-methyl-4-{[1-methyl-2- ({[4-(piperidin-1-ylmethyl)phenyl]carbonyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2-carboxamide 499.6 627 694

N-methyl-4-({1-methyl-2-[4- (morpholin-4-ylmethyl)phenyl]-1H-benzimidazol-5-yl}oxy)pyridine- 2-carboxamide 458.5 628 695

N-methyl-4-({1-methyl-2-[4- (piperidin-1-ylmethyl)phenyl]-1H-benzimidazol-5-yl}oxy) pyridine-2-carboxamide 456.6 628 696

4-({2-[4-({[2- (dimethylamino)ethyl]amino}methyl)phenyl]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 459.6 628 697

4-{[2-(4-{[[2- (dimethylamino)ethyl](methyl) amino]methyl}phenyl)-1-methyl-1H-benzimidazol-5- yl]oxy}-N-methylpyridine-2-carboxamide 473.6628 698

4-[(4-methylpiperazin-1- yl)methyl]-N-{5-[(4-pyridin-3-ylpyrimidin-2-yl)oxy]-1H- benzimidazol-2-yl}benzamide 521.6 629

EXAMPLE 699

[0322] Step 1. Synthesis of{4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide

[0323] To a stirred solution of concentrated nitric acid (22 eq) wasadded 2 h-benzo[d]1,3-dioxolane(1 eq) at 0-10 ° C. for 0.5 h and stirredfor another 0.5 h. To this reaction mixture was then added concentratedsulfuric acid (0.06 eq) drop-wise at 0-10 C° for 0.5 h and stirred at 20C° for 0.5 h. It was then poured on to crushed ice, and the separatedsolid was filtered washed with water and dried to give 5,6-dinitro-2h-benzol[d]1,3-dioxalane. MS:MH⁺ 212

[0324] Step 2. Synthesis of methyl(6-nitro(2h-benzo[3,4-d]1,3-dioxalan-5-yl)amine

[0325] To a stirred solution of methyl amine in ether and ethanol(1.5:1) was added 5,6-dinitro-2 h-benzol[d]1,3-dioxalane and stirred atambient temperature for 24 h. The solvent was evaporated under vacuumand the solid was washed with water and dried to give methyl(6-nitro(2h-benzo[3.4-d]1,3-dioxaln-5-yl))amine. MS: MH⁺ 196

[0326] Step 3. Synthesis of 2-methoxy-4-(methylamino)-5-nitrophenol

[0327] To a stirred solution of methanol was added sodium metal (4.8 eq)slowly at ambient temperature followed by methyl(6-nitro(2h-benzo[3,4-d]1,3-dioxalan-5-yl))amine (1 eq) and stirred for 2 h. Themixture was then refluxed for 0.5 h and diluted with water. Aftercooling it to ambient temperature the separated solid was filtered anddried to give 2-methoxy-4-(methylamino)-5-nitrophenol as a red solid.MS:MH+ 198

[0328] Step 4. Synthesis of{4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide

[0329] To a stirred solution of2-methoxy-4-(methylamino)-5-nitrophenol(1 eq) in N,N-dimethylacetamidewas added potassium-t-butoxide (1.2 eq) and continued stirring atambient temperature until it solidified. To it was then added(3-chlorophenyl)-N-methylcarboxamide (1 eq) and anhydrous potassiumcarbonate (1 eq) and the resulting mixture was heated to 50° C. wherebythe solid liquified. It was then heated to 110° C. for 12 h. Aftercooling to ambient temperature the solvent was distilled off and theresulting solid was extracted using ethyl acetate in a soxhlet apparatusfor 48 h. the organic layer was cooled to 0° C., when the productcrystallized from the ethyl acetate to give{4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide.MS:MH+332

[0330] Step 5. Synthesis of4-{2-[(4-chlrophenyl)amino]-6-methoxy-1-methyl-benzimidazol-5-yloxy)pyridine-2-carboxylicacid

[0331] Totert-butyl4-[3-amino-6-methoxy-4-(methylamino)phenoxy]pyridine-2-carboxylate(1eq) in methanol was added 4-chlorobenzeneisothiocyanate (1 eq) and stirat ambient temperature for 16 h. Formation of the corresponding thioureawas followed by LC/MS. To it was then added iodomethane (1 eq) andheated to 60° C. for 2 h. Formation oftert-butyl4-(2-{[4-chlorophenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylatewas followed by LC/MS. To it in methylene chloride was addedtrifluoroacetic acid and stirred at ambient temperature overnight.Resulting4-(2-{[4-chlorophenylamino)-6-methoxy-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH+=424.

[0332] Step 6. Synthesis of[4-(2-{[4-chlorophenyl)amino-6-methoxy-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide

[0333] To4-(2-{[4-chloropheylamino)-6-methoxy-1-methylbenzimidazol-5-yloxy)-pyridine-2-carboxylicacid(1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2 eq),HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambienttemperature for 16 h. The mixture was then concentrated and partitionedbetween ethyl acetate and water. The organic layer was concentrated andpreparative chromatography yielded[4-(2-{[4-chlorophenyl]amino-6-methoxy-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide.MS: MH+=522.

EXAMPLE 700

[0334] Step 1. Synthesis of4-{2-[(4-bromo-3-methylphenyl)amino]-6-methoxy-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid

[0335] Totert-butyl4-[3-amino-6-methoxy-4-(methylamino)phenoxy]pyridine-2-carboxylate(1eq) in methanol was added 4-bromo-3-methylbenzeneisothiocyanate (1 eq)and stir at ambient temperature for 16 h. Formation of the correspondingthiourea was followed by LC/MS. To it was then added iodomethane (1 eq)and heated to 60° C. for 2 h. Formation oftert-butyl4-(2-{[4-bromo-3-methylphenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylatewas followed by LC/MS. To it in methylene chloride was addedtrifluoroacetic acid and stirred at ambient temperature overnight.Resulting4-(2-{[4-bromo-3-methylphenylamino)-6-methoxy-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid was purified by preparative chromatography. MS: MH+=482.

[0336] Step 2. Synthesis of[4-(2-{[4-bromo-3-methylphenyl)amino-6-methoxy-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide

[0337] To4-(2-{[4-bromo-3-methylpheylamino)-6-methoxy-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylicacid(1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2 eq),HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambienttemperature for 16 h. The mixture was then concentrated and partitionedbetween ethyl acetate and water. The organic layer was concentrated andpreparative chromatography yielded[4-(2-{[4-bromo-3-methylphenyl]amino-6-methoxy-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide.MS: MH+=579.

EXAMPLE 701

[0338] Step 1. Synthesis of4-{3-[3-(3-Isopropyl-phenyl)-thioureaido]-4-methylamino-phenoxy}-pyridine-2-carboxylicacid

[0339] To tert-butyl4-[3-amino-4-(methylamino) phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added3-isopropylbenzeneisothiocyanate (1 eq) and stir at ambient temperaturefor 16 h. Formation of the corresponding thiourea was followed by LC/MS.To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h.Formation of4-{3-[3-(3-Isopropyl-phenyl)-thioureaido]-4-methylamino-phenoxy}-pyridine-2-carboxylate was followed by LC/MS. To it in methylenechloride was added trifluoroacetic acid and stirred at ambienttemperature overnight. Resulting4-(2-{[4-bromo-3-methylphenyl-amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid was purified by preparative chromatography.MS: MH+=437

[0340] Step 2. Synthesis of4-[2-(3-Isopropyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid)2-pyrrolidin-1-yl-ethyl)-amide

[0341] To4-{3-[3-(3-Isopropyl-phenyl)-thioureaido]-4-methylamino-phenoxy}-pyridine-2-carboxylicacid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2eq), EDCI (2 eq), HOAT (1.2 eq) and N,N-diisopropylethylamine (4 eq) andstir at ambient temperature for 16 h. The mixture was then concentratedand partitioned between ethyl acetate and water. The organic layer wasconcentrated and preparative chromatography yielded4-[2-(3-Isopropyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid)2-pyrrolidin-1-yl-ethyl)-amide. MS: MH+=499.

EXAMPLE 702

[0342] Step 1. Synthesis of 3-chloro-4-(2-methyl-5-nitrophenyl)pyridine

[0343] Nitrogen was bubbled through a solution of2-bromo-1-methyl-4-nitrobenzene (1 eq) in dimethoxyethane and water(3:1) for 0.5 h. Bis(diphenylphosphino)ferrocene Palladium(II)chloride(0.05 eq) followed by 3-chloro-4-pyridine boronic acid hydrate (1 eq)and sodium carbonate (3 eq) was added and the mixture was heated to 90°C. for 16 h under nitrogen. The reaction mixture was concentrated andpartitioned between ethyl acetate and water. The organic layer waswashed with brine and dried with sodium sulfate and concentrated.Purification on silica gel gave3-chloro-4-(2-methyl-5-nitrophenyl)pyridine. MS: MH+=248.

[0344] Note: The same procedure was used for Suzuki reaction between thehalopyridines and the nitrophenylboronic acids.

[0345] Boronic acids were synthesized using the following procedure ifcommercially unavailable.

[0346] Step 1a. Synthesis of 2-fluoropyridine boronic acid

[0347] A flame-dried flask was charged with toluene and tetrahydrofuran(4:1) and then with 4-bromo-2-fluoropyridine(1 eq) andtriisopropylborate (1.2 eq) and the flask was cooled to −70° C. Thenn-butyllithium (1.2 eq) was added dropwise over 0.5 h and the mixturewas stirred for 0.5 h at −70° C. The reaction mixture was then broughtto −20° C. and 2N hydrochloric acid was added to it. Formation of2-fluoropyridine boronic acid was seen by LC/MS on warming the mixtureto ambient temperature. The mixture was partitioned between ethylacetate and water. The organic layer was dried with sodium sulfate andconcentrated to yield 2-fluoropyridine boronic acid. MS: MH+=141.

[0348] Step 2. Synthesis of 3-(3-chloro(4-pyridyl)-4-methylphenylamine

[0349] To the mixture containing3-chloro-4-(2-methyl-5-nitrophenyl)pyridine in acetic acid was added Fedust (5 eq) and the resulting mixture was stirred at ambient temperaturefor 6 h. To it was then added saturated sodium carbonate to bring it toneutral pH and extracted with ethyl acetate. The organic layer waswashed with brine and dried with sodium sulfate and concentrated andpassed through a plug of silica to yield3-(3-chloro(4-pyridyl))-4-methylphenylamine. MS: MH+=218.

[0350] Step 3. Synthesis of3-(3-chlro(4-pyridyl))-4-methylbenzeneisothiocyanate

[0351] To 3-(3-chloro(4-pyridyl))-4-methylphenylamine in acetone at 0°C. was added sodium bicarbonate (2 eq) and thiophosgene (2 eq). Themixture was brought to ambient temperature and concentrated andpartitioned between ethyl acetate and water. The organic layer was driedwith sodium bicarbonate and sodium sulfate and concentrated to yield3-(3-chloro(4-pyridyl))-4-methylbenzeneisothiocyanate. MS: MH+=260.

[0352] Step 4. Synthesis of{4-(2-{[3-(3-chloro(4-pyridyl))-4-methylphenyl]amino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide

[0353] To 3-(3-chloro(4-pyridyl))-4-methylbenzeneisothiocyanate(1 eq) inmethanol was added{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1eq) and the resulting mixture was stirred at ambient temperature for 16h. LC/MS shows formation of the corresponding thiourea. To it inmethanol was then added anhydrous ferric chloride (1.5 eq) and stirredfor 3 h. The reaction mixture was then concentrated to half its volumeand brought to neutral pH with IN sodium hydroxide. It was thenextracted with ethyl acetate and the organic layer was washed with brineand dried with sodium sulfate. The crude was then triturated with hotmethanol to yield{4-(2-{[3-(3-chloro(4-pyridyl))-4-methylphenyl]amino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide.MS: MH+=498.

EXAMPLE 703 1. Synthesis of{4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide

[0354] To a stirred solution of concentrated nitric acid (22 eq) wasadded 2 h-benzo[d]1,3-dioxolane(1 eq) at 0-10 ° C. for 0.5 h and stirredfor another 0.5 h. To this reaction mixture was then added concentratedsulfuric acid (0.06 eq) drop-wise at 0-10° C. for 0.5 h and stirred at20 C° for 0.5 h. It was then poured on to crushed ice, and the separatedsolid was filtered washed with water and dried to give 5,6-dinitro-2h-benzol[d]1,3-dioxalane. MS:MH+212

[0355] Step 2. Synthesis of methyl(6-nitro(2h-benzo[3,4-d]1,3-dioxalan-5-yl)amine

[0356] To a stirred solution of methyl amine in ether and ethanol(1.5: 1) was added 5,6-dinitro-2 h-benzol[d]1,3-dioxalane and stirred atambient temperature for 24 h. The solvent was evaporated under vacuumand the solid was washed with water and dried to give methyl(6-nitro(2h-benzo[3.4-d]1,3-dioxaln-5-yl))amine. MS: MH+196

[0357] Step 3. Synthesis of 2-methoxy-4-(methylamino)-5-nitrophenol

[0358] To a stirred solution of methanol was added sodium metal (4.8 eq)slowly at ambient temperature followed by methyl(6-nitro(2h-benzo[3,4-d]1,3-dioxalan-5-yl))amine (1 eq) and stirred for 2 h. Themixture was then refluxed for 0.5 h and diluted with water. Aftercooling it to ambient temperature the separated solid was filtered anddried to give 2-methoxy-4-(methylamino)-5-nitrophenol as a red solid.MS:MH+198

[0359] Step 4. Synthesis of{4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide

[0360] To a stirred solution of2-methoxy-4-(methylamino)-5-nitrophenol(1 eq) in N,N-dimethylacetamidewas added potassium-t-butoxide (1.2 eq) and continued stirring atambient temperature until it solidified. To it was then added(3-chlorophenyl)-N-methylcarboxamide (1 eq) and anhydrous potassiumcarbonate (1 eq) and the resulting mixture was heated to 50° C. wherebythe solid liquified. It was then heated to 110° C. for 12 h. Aftercooling to ambient temperature the solvent was distilled off and theresulting solid was extracted using ethyl acetate in a soxhlet apparatusfor 48 h. The organic layer was cooled to 0° C., when the productcrystallized from the ethyl acetate to give{4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide.MS:MH+332

[0361] Step 5. Synthesis of{4-[3-amino-6-methoxy-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide

[0362] A solution of{4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide.In methanol was hydrogenated with 10% Pd/C. The catalyst was filteredoff and the solvent was concentrated to yield{4-[3-amino-6-methoxy-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide.MS:MH+: 302.

[0363] Step 6. Synthesis of(4-{2-[(4-bromo-3-methylphenyl)amino)]-6-methoxy-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide.

[0364] To a solution of{4-[3-amino-6-methoxy-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide(1 eq) in methanol was added 4-bromo-3-methylbenzeneisothiocyanate (1eq) and stirred at 60° C. for 2 h. Formation of thiourea was followed byLC/MS. To it was added iodomethane (1 eq) and heated to 60° C. for 3 h.The mixture was concentrated and purified on preparative chromatographyto yield(4-{2-[(4-bromo-3-methylphenyl)amino)]-6-methoxy-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide.MS:MH+496.

EXAMPLE 704 Synthesis of(5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy)-(3-pyridyl))-N-methylcarboxamide

[0365]

[0366] Step 1. Synthesis ofmethyl-5-(4-nitrophenoxy)pyridine-3-carboxylate

[0367] The mixture containing methyl-5-hydroxypyridine-3-carboxylate (1eq), Potassium bis(trimethylsilyl)amide (1.2 eq) was stirred inN,N-dimethylformamide for 2 hours at room temperature. To this mixturewas added 1-fluoro-4-nitrobenzene (1.1 eq) and Potassium carbonate (1.2eq) and stirred at 80° C. for 16 h. The reaction mixture was thenconcentrated and partitioned between ethyl acetate and water. Theorganic layer was separated and washed with brine, dried, filtered andconcentrated in vacuum to give brown solid. Purification on silica gelmethyl-5-(4-nitrophenoxy)pyridine-3-carboxylate. MS: MH+=274.

[0368] Step 2. Synthesis ofmethyl5-[4-aminophenoxy]pyridine-3-carboxylate

[0369] The mixture containingmethyl-5-(4-nitrophenoxy)pyridine-3-carboxylate in methanol withcatalytic amount of 10% Pd/C was hydrogenated to yieldmethyl5-[4-aminophenoxy]pyridine-3-carboxylate. MS: MH+=244.

[0370] Step 3. Synthesis ofmethyl-5-[4-(2,2,2-trifluoroacetamino)phenoxy]pyridine-3-carboxylate

[0371] A solution of methyl-5-[4-aminophenoxy]pyridine-3-carboxylate (1eq) in methylene chloride was treated with trifluoroacetic anhydride (1eq) and stirred for 10 minutes at 0 ° C. The mixture was quenched withsaturated sodium bicarbonate solution. The organic layer was separatedand washed with water, brine, dried and evaporated to yieldmethyl-5-[4-(2,2,2-trifluoroacetamino)phenoxy]pyridine-3-carboxylate.MS: MH+=340.

[0372] Step 4. Synthesis ofmethyl5-[3-nitro-4-(2,2,2-trifluoroacetylamino)phenoxy]-pyridine-3-carboxylate

[0373] To a solution ofmethyl-5-[4-(2,2,2-trifluoroacetamino)phenoxy]pyridine-3-carboxylate inacetic acid and acetic anhydride(1:1) at 0° C. was added nitric acidfollowed by sulfuric acid. Followed the reaction by LC and once completeit was partitioned between ethyl acetate. The organic layer was washedwith brine and dried with sodium sulfate and concentrated to yieldmethyl5-[3-nitro-4-(2,2,2-trifluoroacetylamino)-phenoxy]pyridine-3-carboxylate.MS: MH+=385.

[0374] Step 5. Synthesis ofmethyl4-[4-(methylamino)-3-nitrophenoxy]pyridine-3-carboxylate

[0375] To the solution of themethyl5-[3-nitro-4-(2,2,2-trifluoroacetylamino)phenoxy]-pyridine-3-carboxylate(1 eq) in a mixture of toluene, acetonitrile and sodium hydroxidesolution (50%) was added benzyltrimethylarnmonium chloride (1 eq) anddimethyl sulfate (1.2 eq). The biphasic mixture was stirred overnight atroom temperature and evaporated. The mixture was taken up in ethylacetate, washed with water, brine, dried and evaporated. The crude waspurified by column chromatography to affordmethyl4-[4-(methylamino)-3-nitrophenoxy]pyridine-3-carboxylate. MS:MH+=303.

[0376] Step 6. Synthesis ofmethyl5-[3-amino-4-(methylamino)phenoxy]pyridine-3-carboxylate

[0377] The mixture containingmethyl4-[4-(amethylamino)-3-nitrophenoxy]pyridine-3-carboxylate washydrogenated with 10% Pd/C to yieldmethyl5-[3-amino-4-(methylamino)phenoxy]pyridine-3-carboxylate. MS:MH+=273.

[0378] Step 7. Synthesis ofmethyl5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}pyridine-3-carboxylate

[0379] A solution of themethyl5-[3-amino-4-(methylamino)phenoxy]pyridine-3-carboxylate (1 eq) inmethanol (8 ml) was treated with 4-bromophenylisothiocyanate (1 eq) andstirred at 60° C.-65° C. for 2 hours. The reaction mixture was cooleddown to room temperature and methyl iodide (1 eq) was added and stirredovernight at 60° C. The reaction was cooled down to room temperature,evaporated, taken up in ethyl acetate and washed with water and brine,dried, evaporated under reduced pressure. Column chromatography yieldedmethyl5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}pyridine-3-carboxylate.MS: MH+=452

[0380] Step 8. Synthesis of(5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy)-(3-pyridyl))-N-methylcarboxamide

[0381] To a solution ofmethyl5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}pyridine-3-carboxylatein added methylamine and the resulting mixture was stirred at ambienttemperature for 16 h. It was then concentrated and purified bypreparative chromatography to yield(5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy)-(3-pyridyl))-N-methylcarboxamide.MS: MH+=452.

[0382] Each of the compounds 705-746, listed in Table 8 were synthesizedas indicated in the right hand column by the method described in one ofthe Examples 699 or 700. TABLE 8 Synthesized as in Example MolecularStructure Name MH+ Example: 705

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-[(1-ethyl-pyrrolidin-2-yl)methyl]- pyridine-2-carboxamide 594.5 700 706

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-(2-morpholin-4-ylethyl)pyridine-2-carboxamide 596.5 700 707

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-[3-(4-methyl-piperazin-1-yl)propyl]pyridine 2-carboxamide 623.6 700 708

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-1,3-thiazol-2-ylpyridine-2-carboxamide 566.5 700 709

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-[2-(1-methyl-pyrrolidin-2-yl)ethyl]pyridine- 2-carboxamide 594.5 700 710

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-(2-pyrrolidin-1-ylethyl)pyridine-2-carboxamide 580.5 700 711

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-[3-(1H-imidazol-1-yl)propyl]pyridine-2-carboxamide 591.5 700 712

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-[2-(methyloxy)-ethyl]pyridine-2-carboxamide 541.4 700 713

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-(2-hydroxyethyl)-pyridine-2-carboxamide 527.4 700 714

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-(2-piperidin-1-ylethyl)pyridine-2-carboxamide 594.5 700 715

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-(3-piperidin-1-ylpropyl)pyridine-2-carboxamide 608.5 700 716

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-[3-(4-methyl-piperazin-1-yl)propyl]pyridine 2-carboxamide 623.6 700 717

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-(2-pyridin-4-yl-ethyl)pyridine-2-carboxamide 588.5 700 718

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-(2-piperazin-1-yl-ethyl)pyridine-2-carboxamide 595.5 700 719

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-[3-(methyloxy)-propyl]pyridine-2-carboxamide 555.4 700 720

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-propylpyridine-2- carboxamide525.4 700 721

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-ethylpyridine-2- carboxamide511.4 700 722

N-[2-(acetylamino)ethyl]-4- {[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6- (methyloxy)-1H-benzimidazol-5-yl]oxy}pyridine-2-carboxamide 568.4 700 723

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-[2-(2-oxo-imidazolidin-1-yl)ethyl]pyridine-2-carboxamide 595.5 700 724

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-[3-(2-oxo-pyrrolidin-1-yl)propyl]- pyridine-2-carboxamide 608.5 700 725

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-[(1-ethylpyrrolidin-2-yl)methyl]pyridine-2-carboxamide 536.0 699 726

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-(2-morpholin-4-yl-ethyl)pyridine-2-carboxamide 538.0 699 727

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-[3-(4-methylpiperazin-1-yl)propyl]pyridine-2-carboxamide 565.1 699 728

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-1,3-thiazol-2-yl-pyridine-2-carboxamide 508.0 699 729

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5- yl]oxy}-N-[2-(1-methyl-pyrrolidin-2-yl)ethyl]pyridine- 2-carboxamide 536.0 699 730

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-(2-pyrrolidin-1-yl-ethyl)pyridine-2-carboxamide 522.0 699 731

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-[2-(dimethylamino)-ethyl]pyridine-2-carboxamide 496.0 699 732

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-[3-(1H-imidazol-1-yl)-propyl]pyridine-2-carboxamide 533.0 699 733

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-[2-(methyloxy)ethyl]-pyridine-2-carboxamide 482.9 699 734

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-(2-hydroxyethyl)-pyridine-2-carboxamide 468.9 699 735

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-(2-piperidin-1-ylethyl)pyridine-2-carboxamide 536.0 699 736

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-(3-piperidin-1-yl-propyl)pyridine-2-carboxamide 550.1 699 737

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-(3-pyrrolidin-1-yl-propyl)pyridine-2-carboxamide 536.0 699 738

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-(2-pyridin-4-ylethyl)-pyridine-2-carboxamide 530.0 699 739

4-{[2-[(4-chlorophenyl)]- 1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-(2-piperazin- 1-ylethyl)pyridine-2-carboxamide537.0 699 740

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5- yl]oxy}-N-[3-(methyloxy)-propyl]pyridine-2-carboxamide 497.0 699 741

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-propylpyridine-2-carboxamide 466.9699 742

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-ethylpyridine-2-carboxamide 452.9 699743

4-[2-(acetylamino)ethyl]-4- {[2-[(4-chlorophenyl)amino]-1-methyl-6-(methyloxy)-1H- benzimidazol-5-yl]oxy}-pyridine-2-carboxamide 510.0 699 744

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5- yl]oxy}-N-[2-(2-oxo- imidazolidin-1-yl)ethyl]-pyridine-2-carboxamide 537.0 699 745

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide 494.0 699 746

4-{[2-[(4-chlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-[3-(2-oxopyrrolidin-1-yl)propyl]pyridine-2-carboxamide 550.0 699

[0383] Each of the compounds 747-782, listed in the below table weresynthesized as indicated in the right hand column by the methoddescribed in one of the Examples 702 or 703 unless indicated otherwise.TABLE 9 Synthesized as in Example Structure Name MH+ Example: 747

4-{[2-[(4-chlorophenyl)amino]- 1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N- methylpyridine-2-carboxamide 438.9 703 748

4-{[2-[(3-chlorophenyl)amino]- 1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N- methylpyridine-2-carboxamide 438.9 703 749

4-{[2-[(4-bromo-3-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide497.4 703 750

N-methyl-4-({1-methyl-6- (methyloxy)-2-[(4-methyl-phenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 418.5 703 751

4-{[2-(2,3-dihydro-1H-inden-5- ylamino)-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-methylpyridine-2-carboxamide 444.5703 752

N-methyl-4-{[1-methyl-6- (methyloxy)-2-(pyridin-3-yl-amino)-1H-benzimidazol-5-yl]- oxy}pyridine-2-carboxamide 405.4 703 753

4-{[2-{[4-(1,1-dimethylethyl)- phenyl]amino}-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide460.5 703 754

4-{[2-[(2,5-dichlorophenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-methylpyridine-2-carboxamide 473.3703 755

4-{[2-(1,3-benzodioxol-5- ylamino)-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-methylpyridine-2-carboxamide 448.4703 756

4-{[2-[(3-chloro-2-methyl- phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide452.9 703 757

4-{[2-[(4-ethylphenyl)amino]- 1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N- methylpyridine-2-carboxamide 432.5 703 758

4-{[2-[(4-bromophenyl)amino]- 1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N- ethylpyridine-2-carboxamide 483.3 703 759

N-methyl-4-{[1-methyl-6- (methyloxy)-2-({4-[(trifluoro-methyl)oxy]phenyl}amino)-1H- benzimidazol-5-yl]oxy}-pyridine-2-carboxamide 488.4 703 760

4-{[2-[(2,4-dimethylphenyl)- amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]- oxy}-N-methylpyridine-2-carboxamide 432.5703 761

N-methyl-4-(3-{[1-methyl-5- {2-[(methylamino)carbonyl]-pyridin-4-yl}oxy)-1H- benzimidazol-2-yl]amino}-phenyl)pyridine-2-carboxamide 508.6 703 762

4-[(2-{[3-(3-chloropyridin-4- yl)-4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-methylpyridine-2-carboxamide 500.0702 763

4-[(2-{[3-(2-fluoropyridin-4- yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 469.5 702 764

N-methyl-4-[(1-methyl-2-{[3- (1-methylpiperidin-4-yl)-phenyl]amino}-1H-benzimidazol- 5-yl)oxy]pyridine-2-carboxamide 471.6 702765

4-[(2-{[3-(2-fluoropyridin-4- yl)-4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-methylpyridine-2-carboxamide 483.5702 766

N-methyl-4-{[1-methyl-2-({3- [3-(trifluoromethyl)pyridin-4-yl]phenyl}amino)-1H- benzimidazol-5-yl]oxy}- pyridine-2-carboxamide519.5 702 767

N-methyl-4-[(1-methyl-2-{[3- (2-methylpyridin-4-yl)phenyl]-amino}-1H-benzimidazol-5- yl)oxy]pyridine-2-carboxamide 465.5 702 768

N-methyl-4-[(1-methyl-2-{[3- (4-methylpiperazin-1-yl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 472.6 702 769

4-[(2-{[4-chloro-3-(4-methyl- piperazin-1-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-methylpyridine-2-carboxamide 507.0702 770

4-[(2-{[3-(3-chloropyridin-4- yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 485.9 702 771

4-[(2-{[3-(dimethylamino)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 417.5 702 772

4-{[2-({3-(3-chloropyridin-4- yl)-4-[(trifluoromethyl)oxy]-phenyl}amino)-1-methyl-1H- benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide 569.9 702 773

N-methyl-4-[(1-methyl-6- (methyloxy)-2-{[3-(2-methyl-pyridin-4-yl)phenyl]amino}- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 495.6 702 774

N-methyl-4-{[1-methyl-6- (methyloxy)-2-({3-[3-(trifluoro-methyl)pyridin-4-yl]phenyl}- amino)-1H-benzimidazol-5-yl]-oxy}pyridine-2-carboxamide 549.5 702 775

4-{[2-{[3-(3-chloropyridin-4- yl)-4-methylphenyl]amino}-1-methyl-6-(methyloxy)-1H- benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide 530.0 702 776

4-{[2-{[3-(2-fluoropyridin-4- yl)phenyl]amino}-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide499.5 702 777

4-[(2-{[3-(dimethylamino)-4- methylphenyl]amino}-1-methyl-1H-benzimidazol-5- yl)oxy]-N-methylpyridine-2-carboxamide 431.5 1778

N-methyl-4-({1-methyl-2-[(3- pyrimidin-5-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 452.5 702 779

4-{[2-({3-(2-fluoropyridin-4- yl)-4-[(trifluoromethyl)oxy]-phenyl}amino)-1-methyl-1H- benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide 553.5 702 780

4-{[2-({3-(3-fluoropyridin-4- yl)-4-[(trifluoromethyl)oxy]-phenyl}amino)-1-methyl-1H- benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide 553.5 702 781

N-methyl-4-({1-methyl-2-[(3- thien-2-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 456.5 702 782

N-methyl-4-({1-methyl-2-[(3- quinolin-3-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 501.6 702

EXAMPLE 783 Synthesis of[4-(2-{[6-(dimethylamino)(3-pyridyl)]amino}-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide

[0384]

[0385] Step 1. Synthesis of 2-(Dimethylamino-5-nitropyridine:

[0386] 2-Chloro-5-nitropyridine (1.0 eq) and dimethylamine (2 M in EtOH,4.6 eq) in NMP were heated for 2 h at 100° C. The solution was thenpoured slowly into H2O. The filtrate that formed was filtered and driedto give 2-(dimethylamino)-5-nitropyridine.

[0387] Step 2. Synthesis of 2-(Dimethylamino-5-aminopyridine:

[0388] A mixture of 2-(dimethylamino)-5-nitropyridine (1 eq) and 5%palladium on carbon (0.3 eq) in ethanol was stirred at room temperatureand flushed with nitrogen. The reaction vessel was evacuated and purgedwith hydrogen three times. The reaction mixture was left under anatmosphere of hydrogen overnight. Nitrogen was flushed through thereaction and then the reaction was filtered through a celite pad. Thecelite pad was washed with excess ethanol before the solvent was removedby evaporation under reduced pressure to afford2-(dimethylamino)-5-aminopyridine.

[0389] Step 3. Synthesis of 2-(Dimethylamino)-5-isothiocynanatepyridine:

[0390] 2-(Dimethylamino)-5-aminopyridine (1.0 eq) was taken up inacetone and cooled to 0° C. Thiophosgene (1.6 eq) was added dropwise andthe reaction was stirred for 30 minutes at 0 C before the excessthiophosgene and acetone were removed by evaporation under reducedpressure.

[0391] Step 4. Synthesis of[4-(2-{[6-(dimethylamino)(3-pyridyl)]amino}-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide

[0392] A solution of the{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methyl-carboxamide(1.1 eq) in methanol was treated with2-(dimethylamino)-5-isothiocynanate pyridine (1.0 eq) and stirred at 60°C. for 2 hours. Methyl iodide (1 eq) was added and stirred overnight at60° C. The reaction was cooled down to room temperature, evaporated andpurified by reverse phase HPLC. MS: MH+=418.3

EXAMPLE 784

[0393]

[0394] A solution of (1 (eq) and 10% palladium on carbon (0.1 eq) inethyl acetate was stirred at room temperature and flushed with nitrogen.Hydrogen was flushed through the reaction for 2-3 hours or until thereaction was determined to be complete by HPLC. Nitrogen was flushedthrough the reaction for 15 minutes before the reaction was filteredthrough a celite pad. The celite pad was washed with excess ethylacetate and methylene chloride before the combined organic solution wasremoved by evaporation under reduced pressure to afford the product as asolid 2. MS: MH+=207

[0395] A solution of 2 (1 eq) and sodium carbonate (1.5 eq) in acetonewas stirred under nitrogen in an ice bath. Thiophosgene (1.5 eq) wasadded drop wise over 30 minutes. The reaction was stirred for another 30minutes in the ice bath before being removed and allowed to warm to RT.The reaction was stirred at RT for 1.5 h before the reaction solutionwas concentrated under vacuum. Toluene was added to the crude productand removed under vacuum to azetrope off any residual thiophosgene andafford the product 3. MS: MH+=249

[0396] A solution of 3 (1.0 eq) and 4 (1.0 eq) in MeOH was stirred at RTovernight. Ferric chloride (1.2 eq) was added and the resulting reactionmixture was stirred overnight at RT. The reaction mixture wasconcentrated under vacuum. The crude product was partitioned with EtOAcand water and filtered. The layers were separated and the aqueous phasewas neutralized (pH=7) with saturated Na2CO3 solution. The resultingaqueous phase was extracted with EtOAc. The combined organic layers werewashed with brine, dried (Na2SO4), and concentrated to give the desiredproduct 5. MS: MH+=487

[0397] A solution of 5 (1 eq), 6 (1 eq), and sodium carbonate (1.2 eq)in DME/H2O (3:1) was degassed by bubbling argon through the solution for10 minutes. Pd(II)(dppf)C12. MeCl2 (0.1 eq) was added to the reactionsolution and the reaction was sealed. The reaction was heated at 100° C.overnight. The reaction was cooled to RT and ethyl acetate and waterwere added. The organic layer was separated from the aqueous layer. Theaqueous layer was washed once more with ethyl acetate. The organiclayers were combined, dried (Na2SO4), and concentrated under vacuum toyield the desired product 7. MS: MH+=469

[0398] The reaction flask was flame dried and cooled under nitrogen. Asolution of 8 (1.0 eq) in THF was added to the reaction flask followedby triisopropyl borate (1.2 eq). The reaction solution was placed in adry ice/acetone bath to stir at approximately −72° C. N-butyl lithium(1.5 eq, 2.5M solution in hexane) was added drop wise over 40 minutes.The reaction solution was stirred for another 30 minutes in the dryice/acetone bath. The reaction solution was then transferred to asaturated NaCl/dry ice bath to stir at approx. −25° C. and stirred for20 minutes before 2N HCl (2.0 eq) was added. The reaction solution wasthen removed from the bath to stir and warm to RT. The organic andaqueous layers were separated. The aqueous layer was washed once withethyl acetate. The organic layers were combined, dried (Na2SO4), andconcentrated under vacuum to yield the desired product 9. MS: MH+=141

[0399] Each of the compounds 785-802, listed in the below table weresynthesized as indicated in the right hand column by the methoddescribed in one of the Examples 783 or 784. TABLE 10 Synthesized Ex- asin ample Structure Name MH+ Example: 785

4-({2-[(4-fluoro-3-pyridin-3- ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 469.5 784 786

4-({2-[(4-fluoro-3-pyridin-4- ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 469.5 784 787

4-({2-[(4-chloro-3-pyridin-4- ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 485.9 784 788

4-[(2-{[4-chloro-3-(2- fluoropyridin-4-yl)phenyl]- amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N-methyl-pyridine-2-carboxamide 503.9 784 789

4-({2-[(4-chloro-3-pyridin-2- ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 485.9 784 790

4-({2-[(4-chloro-3-pyridin-3- ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 485.9 784 791

4-[(2-{[4-chloro-3-(3- fluoropyridin-4-yl)phenyl]- amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 503.9 784 792

4-[(2-{[4-chloro-3-(6- fluoropyridin-3-yl)phenyl]- amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 503.9 784 793

4-{[2-({4-chloro-3-[6- (methyloxy)pyridin-3-yl]-phenyl}amino)-1-methyl-1H- benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide 516 784 794

4-[(2-{[3-(6-fluoropyridin-3-yl)- 5-(trifluoromethyl)phenyl]-amino}-1-methyl-1H- benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide 537.5 784 795

4-[(2-{[3-(3-fluoropyridin-4-yl)- 5-(trifluoromethyl)phenyl]-amino}-1-methyl-1H- benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide 537.5 784 796

4-[(2-{[3-(2-fluoropyridin-4-yl)- 5-(trifluoromethyl)phenyl]-amino}-1-methyl-1H- benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide 537.5 784 797

N-methyl-4-[(1-methyl-2-{[3- [6-(methyloxy)pyridin-3-yl]-5-(trifluoromethyl)phenyl]amino}- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 549.5 784 798

N-methyl-4-[(1-methyl-2-{[3- pyridin-2-yl-5-(trifluoromethyl)-phenyl]amino}-1H- benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 519.5784 799

N-methyl-4-[(1-methyl-2-{[3- pyridin-3-yl-5-(trifluoromethyl)-phenyl]amino}-1H- benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 519.5784 800

N-methyl-4-[(1-methyl-2-{[3- pyridin-4-yl-5-(trifluoromethyl)-phenyl]amino}-1H- benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 519.5784 801

4-[(2-{[6-(dimethylamino)- pyridin-3-yl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 418.5 783 802

N-methyl-4-({1-methyl-2-[(6- pyrrolidin-1-ylpyridin-3-yl)-amino]-1H-benzimidazol-5-yl}- oxy)pyridine-2-carboxamide 444.5 783

EXAMPLE 803

[0400]

[0401] Step 1.4-[2-(3-Isopropyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid (2-phenylmethanesulfonylamino-ethyl)-amide

[0402] To a mixture containing4-[2-(3-Isopropyl-phenylamino)-1-methyl-1H-benzo-imidazol-5-yloxy]-pyridine-2-carboxylicacid (2-amino-ethyl)-amide (1 eq) (prepared using previously describedexample 3), K2CO3 (5 eq), (0.2 M in a 5:1 mixture of acetonitrile andwater) were added a-toluenesulfonyl chloride (1 eq) via syringe. Theresulting heterogeneous mixture was allowed to stir for 1 hour at roomtemperature. The mixture was then diluted with water and extracted withdichloromethane. The organics were washed with water and a saturatedsolution of sodium chloride, dried with sodium sulfate and concentratedin vacuo to viscous oil. Purification by chromatography yielded4-[2-(3-Isopropyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid (2-phenylmethanesulfonylamino-ethyl)-amide. MS: MH+599

[0403] The compounds shown in the following Table (Examples 804-812)were prepared from following the procedure described for Example 803.TABLE 11 Example Structure Name MH+ 804

4-[(1-methyl-2-{[3-(1-methyl- ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-{2- [(methylsulfonyl)amino]-ethyl}pyridine-2-carboxamide 523.6 805

4-[(1-methyl-2-{[3-(1-methyl- ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2- {[(phenylmethyl)sulfonyl]-amino}ethyl)pyridine- 2-carboxamide 599.7 806

4-[(1-methyl-2-{[3-(1-methyl- ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2- {[(trifluoromethyl)sulfonyl]-amino}ethyl)pyridine- 2-carboxamide 577.6 807

4-[(1-methyl-2-{[3-(1-methyl- ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-{2- [(phenylsulfonyl)amino]ethyl}-pyridine-2-carboxamide 585.7 808

4-[(1-methyl-2-{[3-(1-methyl- ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-{2- [(propylsulfonyl)amino]-ethyl}pyridine-2-carboxamide 551.7 809

4-[(1-methyl-2-{[3-(1-methyl- ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2- {[(4-methylphenyl)sulfonyl]-amino}ethyl)pyridine- 2-carboxamide 599.7 810

4-[(1-methyl-2-{[3-(1-methyl- ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-{2- [(thien-2-ylsulfonyl)amino]-ethyl}pyridine-2-carboxamide 591.7 811

N-(2-{[(1-methylethyl)- sulfonyl]amino}ethyl)-4-[(1-methyl-2-{[3-(1-methylethyl)- phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 551.7 812

N-(2-{[(5-chlorothien-2-yl)- sulfonyl]amino}ethyl)-4-[(1-methyl-2-{[3-(1-methylethyl)- phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 626.2

EXAMPLE 813

[0404]

[0405] Step 1. 4-{2-(3-(1-Benzyl-1H-[1,2,3] triazol-4-yl)-phenylamino]-1-methyl-1H-benzoimidazol-5-yloxy}-pyridine-2-carboxylic acidmethyl amide

[0406] To a mixture of4-[2-(3-Ethynl-phenylamino)-1-methyl-1H-benzoimidazol-5-yl-oxy]-pyridine-2-carboxylicacid methylamide (1 eq)(prepared using previously described example 2),benzyl azide (1 eq) in t-butanol (0.1 M) was added sodium ascorbate(0.05 eq), and copper (II) sulfate pentahydrate (0.01 eq). The resultingmixture was allowed to stir for 1 hour at room temperature. The mixturewas then diluted with water and the solid collect via suctionfiltration. MS: MH+531

EXAMPLE 814

[0407]

[0408] Step 1. Synthesis of 6-Nitro-indole-1-carboxylic acid t-butylester

[0409] To a stirring solution of 6-nitroindole (1 eq) in dichloromethane(0.3M) and DMF (3.1M), was added di-t-butyl dicarbonate (2 eq) followedby the addition of 4-(dimethyl amino) pyridine (1 eq). Resultingsolution was allowed to stir overnight at room temperature. Thedichloromethane was then removed on a rotovap and remaining solutiondiluted with water and extracted with ethyl acetate. Organics werewashed with 10% citric acid solution, saturated solution of sodiumchloride, saturated solution of sodium bicarbonate, saturated solutionof sodium chloride and dried with sodium sulfate. Ethyl acetate was thenremoved in vacuo. Ethyl ether was then added and a brown solid wascollected by suction filtration to yield 6-Nitro-indole-1-carboxylicacid t-butyl ester. MS: MH+263

[0410] Step 2. Synthesis of 6-Amino-2,3-dihdro-indole-1-carboxylic acidt-butyl ester

[0411] 6-Nitro-indole-1-carboxylic acid t-butyl ester (1 eq) wasdissolved in methanol (0.1M), to this solution was added palladium oncarbon (0.1 eq) in methanol under nitrogen. A hydrogen atmosphere wasthen inserted and resulting mixture allowed to stir for 3 hours at roomtemperature. The reaction mixture was then filtered through celite andsolvent removed in vacuo to afford6-Amino-2,3-dihdro-indole-1-carboxylic acid t-butyl ester as a whitesolid. MS: MH+235

[0412] Step 3. Synthesis of6-Isothiocyanate-2,3-dihydro-indole-1-carboxylic acid t-butyl ester

[0413] Thiophosgene (1.1 eq) was added to a stirred suspension of6-Amino-2,3-dihdro-indole-1-carboxylic acid t-butyl ester (1 eq), sodiumcarbonate (10 eq), and dichloromethane: water 3:1 by volume at 0° C. Theresulting mixture was allowed to stir for 2 hours at 0° C. The mixturewas diluted with water and organics separated and washed with water,saturated solution of sodium chloride and dried with sodium sulfate,solvent removed in vacuo to afford6-Isothiocyanate-2,3-dihydro-indole-1-carboxylic acid t-butyl ester asorange oil.

[0414] Step 4. Synthesis of4-[2-(2,3-Dihydro-1H-indol-6-ylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid methylamide.

[0415] To a solution of4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic acid methylamide(1 eq) in methanol (0.1 M) was added palladium on carbon (0.1 eq) undernitrogen. The atmosphere was exchanged for hydrogen (1 atm) and theresulting suspension allowed to stir for 2 hours at room temperature.The mixture was filtered through celite and added to6-Isothiocyanate-2,3-dihydro-indole-1-carboxylic acid t-butyl ester (1eq). The resulting solution was allowed to stir overnight. Iron (III)chloride(2 eq) in methanol was added and the solution turns deep red incolor. This solution was allowed to stir for 3 hours at roomtemperature. Methanol was then removed in vacuo; the resulting oil wasdiluted with water and extracted with dichloromethane. Organics werewashed with saturated sodium bicarbonate solution, water, and saturatedsodium chloride solution and dried with sodium sulfate. Solvent wasremoved in vacuo. To the resulting oil was added toluene and heated toreflux, solution was cooled to room temperature and a solid wascollected after 3 days by suction filtration to afford4-[2-(2,3-Dihydro-1H-indol-6-ylamino)-1-methyl-1H-benzoimidazol-5-yloxy)-pyridine-2-carboxylicacid methylamide. MS: MH+415

EXAMPLE 815

[0416]

[0417] Step 1. Synthesis of4-{1-Methyl-2-[1-(4-morpholin-4-yl-butylryl)-2,3-dihydro-1H-indol-6-ylamino]-1H-benzoimidazol-5-yloxy}-pyridine-2-carboxylicacid methylamide

[0418] To mixture containing4-[2-(2,3-Dihydro-1H-indol-6-ylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid methylamide (1 eq)(previously prepared using example 1), EDCI (2eq), HOAT (1.2 eq), DIEA (4 eq) was added THF. The mixture was allowedto stir overnight at room temperature under nitrogen. The mixture wasthen diluted with water, extracted with ethyl acetate. Organics werewashed with water, then saturated solution of sodium chloride and driedwith sodium sulfate, filtered and the solvent was removed in vacuo.Purification by chromatography yielded4-{1-Methyl-2-[1-(4-morpholin-4-yl-butylryl)-2,3-dihydro-1H-indol-6-ylamino]-1H-benzoimidazol-5-yloxy}-pyridine-2-carboxylicacid methylamide. MS: MH+570

[0419] The compounds shown in the following table (Examples 816-819)were prepared from following the procedure described for Example 815.TABLE 12 Example Structure Name MH+ 816

4-{[2-(2,3-dihydro-1H- indol-6-ylamino)-1- methyl-1H-benz-imida-zol-5-yl]oxy}-N-methyl- pyridine-2-carboxamide 415.5 817

N-methyl-4-[(1-methyl- 2-{[1-(3-pyridin-4- ylpropanoyl)-2,3-dihydro-1H-indol-6-yl ]amino}-1H-benz-imidazol-5-yl)oxy]pyridine-2-carboxamide 548.6 818

4-{[2-({1-[3-(1H- imidazol-4-yl)- propanoyl]-2,3-dihydro-1H-indol-6-yl}amino)-1- methyl-1H-benz-imida- zol-5-yl]oxy}-N-methyl-pyridine-2-carboxamide 537.6 819

N-methyl-4-[(1- methyl-2-{[1-(4- morpholin-4-ylbutanoyl)-2,3-dihydro-1H-indol-6- yl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide 570.7

EXAMPLE 820

[0420]

[0421] Step 1. Synthesis of4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic acid:

[0422] A stirring solution of4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic acid tert-butylester in trifluoroacetic acid was treated with two drops of water atroom temperature for 3-4 hours or when the reaction was determined to becomplete by HPLC. The reaction was evaporated under reduced pressure toafford the product as a red-orange oil. Addition of ethyl ether,sonication, and filtration captures the product as a light pink solid.LCMS m/z 290.1 (MH+), tR=1.71 min.

[0423] Step 2. Synthesis of4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic acid(2-hydroxy-ethyl)-amide:

[0424] To a suspension of the4-(4-methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic acid (1 eq) indry THF, EDC-HCl (1.2 eq), HOAT (1.2 eq), and diisopropylethylamine (3eq) were added. The suspension was stirred for 10 minutes whereupon2,2-dimethyl-oxazolidine (1.1 eq) was added and the solution is allowedto stir overnight. The mixture was then diluted with ethyl acetate andwashed with water. The aqueous layer was washed with ethyl acetate, theorganic layers combined, dried over MgSO4, filtered, and concentrated.LCMS m/z 333.2 (MH+), tR=2.1 min.

[0425] Step 3. 4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carboxylicacid (2-hydroxy-ethyl)-amide:

[0426] A solution of4-(4-methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic acid(2-hydroxy-ethyl)-amide (1 eq) and 10% palladium on carbon (0.1 eq) inmethanol was stirred at room temperature and flushed with nitrogen.Hydrogen was flushed through the reaction for 1-2 hours or until thereaction was determined to be complete by HPLC. Nitrogen was flushedthrough the reaction for 15 minutes before the reaction was filteredthrough a celite pad. The celite pad was washed with excess methanolbefore it was all removed by evaporation under reduced pressure toafford the product as a light yellow solid. LCMS m/z 303.2 (MH+), tR=1.5min.

[0427] Step 4.4-[1-Methyl-2-(3-trifluoromethylsulfanyl-phenylamino)-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid (2-hydroxy-ethyl)-amide:

[0428] A flask was charged with3-(trifluoromethylthio)phenylisothiocyanate (1 eq),4-(3-amino-4-methylamino-phenoxy)-pyridine-2-carboxylic acid(2-hydroxy-ethyl)-amide (1 eq), and MeOH. The reaction was maintained atrt overnight. Ferric chloride, (1.5 eq) was added and the resulting redreaction mixture was stirred overnight. The reaction was partitionedwith EtOAc and water, and filtered through Celite. The layers wereseparated and the aqueous phase was neutralized with saturated Na2CO3solution. The resulting aqueous phase was extracted with EtOAc and themixture was filtered through Celite. The phases were separated and theaqueous phase was again extracted and filtered. The combined organiclayers were washed with brine, dried (MgSO4), filtered, and concentratedto give a brown solid. The crude residue was purified by reverse phaseHPLC. LCMS m/z 504.1 (MH+), tR=3.7 min.

EXAMPLE 821

[0429]

[0430] Step 1. Synthesis of4-[2-(4-Fluoro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid tert-butyl ester:

[0431] A round bottom flask was charged with4-fluorophenylisothiocyanate (1 eq),4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carboxylic acid tert-butylester (1 eq), and MeOH. The reaction was maintained stirring at roomtemperature overnight. Ferric chloride, (1.5 eq) was added and theresulting mixture was stirred overnight. The reaction was partitionedwith EtOAc and water, and filtered through Celite. The layers wereseparated and the aqueous phase was neutralized with saturated Na2CO3solution. The resulting aqueous phase was extracted with EtOAc and themixture was filtered through Celite. The phases were separated and theaqueous phase was again extracted and filtered. The combined organiclayers were washed with brine, dried over MgSO4, filtered, andconcentrated to give a brown solid. The crude residue was purified bytrituration in hot toluene to furnish the desired product. LCMS m/z435.6 (MH+), tR=2.12 min.

[0432] Step 2. Synthesis of4-[2-(4-Fluoro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid:

[0433] A stirring solution of4-[2-(4-Fluoro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid tert-butyl ester in trifluoroacetic acid was treated with two dropsof water at room temperature for 3-4 hours or when the reaction wasdetermined to be complete by HPLC. The reaction was evaporated underreduced pressure and then ether was added to the residue, which was thensonicated for 30 minutes. Filtration and washing with ether yields thedesired acid in quantitative yield. LCMS m/z 379.4 (MH+), tR=1.74 min.

[0434] Step3. Synthesis of{5-[2-(1H-Benzoimidazol-2-yl)-pyridin-4-yloxy]-1-methyl-1H-benzoimidazol-2-yl}-(4-fluoro-phenyl)-amine:

[0435] To a suspension of4-[2-(4-Fluoro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid (1 eq) in dry THF, EDC-HCl (1.2 eq), HOAT (1.2 eq), anddiisopropylethylamine (3 eq) were added. The suspension was stirred for10 minutes whereupon phenylenediamine (1.1 eq) was added and thesolution is allowed to stir overnight. The mixture was then diluted withethyl acetate and washed with water. The aqueous layer was washed withethyl acetate, the organic layers combined, dried over MgSO4, filtered,and concentrated. Acetic acid was added to the residue followed bysodium acetate (1.1 eq). The mixture was heated for 3 hours at 70° C.,whereupon the solution is concentrated and the residue purified byreverse phase HPLC to afford the desired product. LCMS m/z 451.5 (MH+),tR=1.92 min.

Synthesis of Side Chains Ether Substituted Phenylenediamines

[0436]

4-(3-Bromopropoxy)-2-nitrophenylamine

[0437] A flask is charged with 4-amino-3-nitrophenol 1 (1 eq), K₂CO₃ (2eq), and 2-butanone. 1,3-dibromopropane 2 (1.5 eq) is added and themixture is heated at 80° C. for 18 hours. After cooling, the mixture isfiltered concentrated and water is added. The solution is then extractedwith CH₂Cl₂ (×3), the organic layer concentrated, and the solidrecovered washed with pentane to yield the desired product 3. LCMS m/z275.1 (MH+), R_(t) 2.74 minutes.

2-Nitro4-(3-pyrrolidinylpropoxy)phenylamine

[0438] 4-(3-bromopropoxy)-2-nitrophenylarnine 1 (1 eq) was heated to 70°C. with pyrrolidine 2 (5 eq) in MeCN with Cs₂CO₃ (2 eq) and Bu₄NI (0.1eq) for 48 hours. The reaction mixture was cooled, filtered, andconcentrated. The residue is dissolved in CH₂Cl₂, and washed with water.The organic layer is concentrated yielding the desired product 3. LCMSm/z 266.2 (MH+), R_(t) 1.51 minutes.

4-(3-Pyrrolidinylpropoxy)benzene-1,2-diamine

[0439] To a solution 2-Nitro-4-(3-pyrrolidinylpropoxy)phenylamine 1 inEtOH, Pd/C (0.1 eq) is added. The reaction vessel is repeatedly purged(×3) with nitrogen, and then stirred under a hydrogen atmosphere for 18h. The product is filtered through a Celite plug, and the plug washedwith 25 mL of EtOH, to yield 2. LCMS 236.2 R_(t) 0.94 min.

3-Fluoro4-amino substituted phenylenediamines

[0440]

1. Synthesis of 2-Fluoro-3-(4-methyl-piperazin-1-yl)-6-nitro-phenylamine

[0441] A solution of N-methylpiperazine (1.0 eq), NMP, triethylamine(3.0 eq) and 5,6-difluoro-2-nitroaniline (1.0 eq) were heated at 90° C.for 1 hour. The reaction was allowed to cool to room temperature andthen poured into water and let stand for 1 hour. The resulting solid wascollected and dried and utilized without further purification. MH+=255.3

2. Synthesis of 3-Fluoro-4-(4-methyl-piperazin-1-yl)-benzene-1,2-diamine

[0442] To a solution Synthesis of2-fluoro-3-(4-methyl-piperazin-1-yl)-6-nitro-phenylamine in EtOH, Pd/C(0.1 eq) is added. The reaction vessel is repeatedly purged (×3) withnitrogen, and then stirred under a hydrogen atmosphere for 18 h. Theproduct is filtered through a Celite plug, the plug washed with 25 mL ofEtOH, to yield the desired diamine. LCMS 225.3 Rt 0.45 min.

4-Amino substituted phenylenediamines (a)

[0443]

Synthesis of 5-(4-Methyl-piperazin-1-yl)-2-nitro-phenylamine

[0444] A solution of N-methylpiperazine (1.0 eq), NMP, triethylamine(3.0 eq) and 5-fluoro-2-nitrophenylamine (1.0 eq) were heated at 90° C.for 1 hours. The reaction was allowed to cool to room temperature andthen poured into water and let stand for 12 hours. The resulting solidwas collected and dried and utilized without further purification.MH+=237.3.

Synthesis of 4-(4-Methyl-piperazin-1-yl)-benzene-1,2-diamine

[0445] To a solution 5-(4-Methyl-piperazin-1-yl)-2-nitro-phenylamine inEtOH, Pd/C (0.1 eq) is added. The reaction vessel is repeatedly purged(×3) with nitrogen, then stirred under a hydrogen atmosphere for 18 h.The product is filtered through a Celite plug, the plug washed with 25mL of EtOH, to yield the desired diamine. LCMS 207.3 Rt 0.25 min.

4-Amino substituted phenylenediamines (b)

[0446]

Synthesis of 5-(4-Cyclopentyl-piperazin-1-yl)-2-nitro-phenylamine

[0447] 1. A solution of N-cyclopentylpiperazine (1.0 eq), NMP,triethylamine (3.0 eq) and 5-fluoro-2-nitrophenylamine (1.0 eq) wereheated at 90° C. for 1 hours. The reaction was allowed to cool to roomtemperature and then poured into water and let stand for 12 hours. Theresulting solid was collected and dried and utilized without furtherpurification. MH+=291.4.

2. Synthesis of 4-(4-Cyclopentyl-piperazin-1-yl)-benzene-1,2-diamine

[0448] To a solution5-(4-Cyclopentyl-piperazin-1-yl)-2-nitro-phenylamine in EtOH, Pd/C (0.1eq) is added. The reaction vessel is repeatedly purged (×3) withnitrogen, then stirred under a hydrogen atmosphere for 18 h. The productis filtered through a Celite plug, the plug washed with 25 mL of EtOH,to yield the desired diamine. MH+=261.3.

[0449] Step 1. Synthesis of 4-Chloro-pyridine-2-carboxylic aciddimethylamide:

[0450] A solution of 4-chloro-pyridine-2-carbonyl chloride (1 eq) indichloromethane was cooled to 0° C., whereupon triethylamine (2 eq) wasadded followed by dimethylamine (2 eq, 2M solution in THF). The solutionwas allowed to warm to room temperature and let stir overnight. It wasthen washed with 1M NaOH. The separated organic layer is dried overMgSO4, filtered, and concentrated to yield the desired product. HPLC,1.82 min; MS: MH+=185.6

[0451] Step 2. Synthesis of4-(4-Amino-3-nitro-phenoxy)-pyridine-2-carboxylic acid dimethylamide:

[0452] A mixture containing 4-amino-3-nitrophenol (1 eq) and potassiumbis(trimethylsilyl)amide (2 eq) was stirred in dimethylformamide for 2hours at room temperature. To this mixture was added4-Chloro-pyridine-2-carboxylic acid dimethylamide (1 eq) and potassiumcarbonate (1.2 eq) and then it was stirred at 90° C. for 3 days. Thereaction mixture was then concentrated before partitioning between ethylacetate and water. The organic layer was separated, washed with brine,dried, filtered and concentrated in vacuum to give brown solid.Purification by flash chromatography with ethyl acetate and hexane (1:1)gave the desired product as a yellow syrup. HPLC, 1.69 min; MS:MH+=303.1.

[0453] Step 3. Synthesis of4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic aciddimethylamide:

[0454] A solution of 4-(4-Amino-3-nitro-phenoxy)-pyridine-2-carboxylicacid dimethylamide (1 eq) in methylene chloride was treated withtrifluoroacetic anhydride (1 eq) and stirred for 10 minutes at 0° C. Themixture was quenched with satd. NaHCO₃ solution. The organic layer wasseparated and washed with water, brine, dried, filtered and evaporated.MS: MH+=399.0

[0455] To the solution of the trifluoroacetamide (1 eq) in a mixture oftoluene, acetonitrile and sodium hydroxide solution (50%) was addedbenzyltrimethylammonium chloride (1 eq) and dimethyl sulfate (1.2 eq).The biphasic mixture was stirred overnight at room temperature. Themixture was taken up in ethyl acetate, washed with water, brine, driedand evaporated. The crude was purified by flash chromatography elutingwith 5% methanol in dichloromethane to afford the desired product. HPLC,2.14 min; MS: MH+=317.3

[0456] Step 4. Synthesis of4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carboxylic aciddimethylamide:

[0457] The solution of4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic aciddimethylamide in methanol was treated with 10% palladium on carbon andstirred under hydrogen atmosphere for 3 hours at room temperature. Themixture was purged with nitrogen and then was filtered through celiteand the filtrate was concentrated to provide the diamine. HPLC, 1.17min; MS: MH+=287.1

[0458] Step 5. Synthesis of4-[2-(2,6-Difluoro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid dimethylamide:

[0459] A solution of the4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carboxylic aciddimethylamide (1 eq) in methanol was treated with2,6-difluorophenylisothiocyanate (1 eq) and stirred overnight. To thereaction mixture, methyl iodide (1 eq) was added and stirred overnightat 60° C. The reaction was cooled down to room temperature, evaporated,and the residue purified by reverse phase HPLC. HPLC, 1.66 min; MS:MH+=424.1

[0460] Each of the compounds 823-984, listed in the below table weresynthesized as indicated in the right hand column by the methoddescribed herein. TABLE 13 Synthesized Example Structure Name MH+ as inEx.: 823

4-({2-[(2,6-difluorophenyl)- amimo]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N,N- dimethylpyridine-2-carboxamide 424.1 822 824

N,N-dimethyl-4-[(1-methyl-2- {[2-(trifluoromethyl)phenyl]-amino}-1H-benzimidazol-5- yl)oxy]pyridine-2-carboxamide 456.4 822 825

4-({2-[(4-ethylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}-oxy)-N,N-dimethylpyridine-2- carboxamide 416.5 822 826

4-({2-[(3,5-difluorophenyl)- amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N,N- dimethylpyridine-2-carboxamide 424.4 822 827

4-({2-[(2,4-dimethylphenyl)- amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N,N- dimethylpyridine-2-carboxamide 416.5 822 828

N,N-dimethyl-4-{[1-methyl-2- ({2-[trifluoromethyl)oxy]-phenyl}amino)-1H-benz- imidazol-5-yl]oxy}pyridine-2- carboxamide 472.4822 829

4-({2-[(2,5-difluorophenyl)- amino]-1-methyl-1H-benzimidazoi-5-yl}oxy)-N,N- dimethylpyridine-2-carboxamide 424.4 822 830

4-({2-[(3-ethylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}-oxy)-N,N-dimethylpyridine-2- carboxamide 416.5 822 831

4-[(2-{[2-chloro-5-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N,N-dimethylpyridine-2- carboxamide490.9 822 832

4-[(2-{[2-fluoro-5-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N,N-dimethylpyridine-2- carboxamide474.4 822 833

N,N-dimethyl-4-[(1-methyl-2- {[2-(methylthio)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 434.5 822 834

4-({2-[(2,4-difluorophenyl)- amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N,N- dimethylpyridine-2-carboxamide 424.4 822 835

4-({2-[(2,3-dimethylphenyl)- amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N,N- dimethylpyridine-2-carboxamide 416.5 822 836

4-[(2-{[4-chloro-2-(trifluoro- methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N,N-dimethylpyridine-2- carboxamide490.9 822 837

4-({2-[(3-chloro-2-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N,N- dimethylpyridine-2-carboxamide 436.9 822 838

4-[(2-{[5-chloro-2-(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N,N- dimethylpyridine-2-carboxamide 452.9 822 839

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N,N- dimethylpyridine-2-carboxamide 448.5 822 840

N,N-dimethyl-4-[(1-methyl-2- {[5-methyl-2-(methyloxy)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 432.5822 841

N,N-dimethyl-4-[(1-methyl-2- {[4-(methyloxy)-1,1′-biphenyl-3-yl]amino}-1H-benzimidazol- 5-yl)oxy]pyridine-2-carbox- amide 494.6 822842

4-[(2-{[3,4-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N,N- dimethylpyridine-2-carboxamide 448.5 822 843

N,N-dimethyl-4-[(1-methyl-2- {[2-(methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 418.5 822 844

4-[(2-{[5-chloro-2,4-bis(methyl- oxy)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]- N,N-dimethylpyridine-2- carboxamide 482.9 822845

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(1- methylpyrrolidin-2-yl)ethyl]-pyridine-2-carboxamide 531.6 372 846

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2- (dimethylamino)ethyl]pyridine-2-carboxamide 491.6 372 847

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3- (methyloxy)propyl]pyridine-2- carboxamide492.5 372 848

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2- (methyloxy)ethyl]pyridine-2- carboxamide478.5 372 849

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(4- methylpiperazin-1-yl)propyl]-pyridine-2-carboxamide 560.7 372 850

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(3- morpholin-4-ylpropyl)pyridine-2-carboxamide 547.6 372 851

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- (1,2,2,6,6-pentamethylpiperidin-4-yl)pyridine-2-carboxamide 573.7 372 852

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2- morpholin-4-ylethyl)pyridine-2- carboxamide533.6 372 853

4-[(2-{[3,5-bis(methyloxy)- phenyl[amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methyl-N-propylpyridine-2- carboxamide 476.5372 854

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methyl-N-[2-(methyloxy)-ethyl]pyridine-2-carboxamide 492.5 372 855

4-[(2-{[3,5-bis(methyloxy)- phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2- (dimethylamino)ethyl]-N-methylpyridine-2-carboxamide 505.6 372 856

5-{[2-(1H-benzimidazol-2-yl)- pyridin-4-yl]oxy}-N-[3,5-bis-(methyloxy)phenyl]-1-methyl- 1H-benzimidazol-2-amine 493.5 821 857

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(1H-imidazol-4- yl)ethyl]pyridine-2-carboxamide 472.5 372858

N-[2-(dimethylamino)ethyl]-4- ({2-[(2-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5- yl}oxy)pyridine-2-carboxamide 449.5 372 859

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(1-methyl- pyrrolidin-2-yl)ethyl]pyridine-2- carboxamide489.6 372 860

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(1H-indol-3-yl)- ethyl]pyridine-2-carboxamide 521.6 372 861

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5- yl}oxy)-N-[3-(methyloxy)- propyl]pyridine-2-carboxamide 450.5 372 862

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(methyloxy)- ethyl]pyridine-2-carboxamide 436.5 372 863

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-pyridin-4-ylethyl)- pyridine-2-carboxamide 483.5 372 864

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(4-methyl- piperazin-1-yl)propyl]pyridine- 2-carboxamide518.6 372 865

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(3-morpholin-4-yl- propyl)pyridine-2-carboxamide 505.6 372 866

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-(2-pyridin- 4-ylethyl)pyridine-2-carbox- amide 497.5372 867

N-[(1-ethylpyrrolidin-2-yl)- methyl]-4-({2-[(2-fluorophenyl)-amino]-1-methyl-1H-benz- imidazol-5-yl}oxy)pyridine-2- carboxamide 489.6372 868

4-({2-[(2-fluorophenyl)amino]- yl-methyl-1H-benzimidazol-5-yl}oxy)-N-(1,2,2,6,6-penta- methylpiperidin-4-yl)pyridine-2- carboxamide531.6 372 869

4-({2-[(2-fluorophenyl)amino]- yl-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-propyl- pyridine-2-carboxamide 434.5 372 870

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-morpholin-4-yl- ethyl)pyridine-2-carboxamide 491.5 372 871

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-[2-(methyl- oxy)ethyl]pyridine-2-carbox- amide 450.5372 872

4-({2-[(2-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-(1-methyl- piperidin-4-yl)pyridine-2- carboxamide489.6 372 873

N-[2-(dimethylamino)ethyl]-4- ({2-[(2-fluorophenyl)amino]-1-ethyl-1H-benzimidazol-5-yl}- oxy)-N-methylpyridine-2- carboxamide 463.5372 874

N-[2-(1H-imidazol-4-yl)ethyl]- 4-[(1-methyl-2-{[2-(methyloxy)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 484.5372 875

N-[2-(dimethylamino)ethyl]-4- [(1-methyl-2-{[2-(methyloxy)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 461.5372 876

4-[(1-methyl-2-{[2-(methyloxy)- phenyl]amino}-1H-benz-imidazol-5-yl)oxy]-N-[2-(1- methylpyrrolidin-2-yl)ethyl]-pyridine-2-carboxamide 501.6 372 877

N-[2-(1H-indol-3-yl)ethyl]-4- [(1-methyl-2-{[2-(methyloxy)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 533.6372 878

4-[(1-methyl-2-{[2-(methyloxy)- phenyl]amino}-1H-benz-imidazol-5-yl)oxy]-N-[3- (methyloxy)propyl]pyridine-2- carboxamide 462.5372 879

4-[(1-methyl-2-{[2-(methyloxy)- phenyl]amino}-1H-benz-imidazol-5-yl)oxy]-N-[2- (methyloxy)ethyl]pyridine-2- carboxamide 448.5372 880

4-[(1-methyl-2-{[2-(methyloxy)- phenyl]amino}-1H-benz-imidazol-5-yl)oxy]-N-(2- pyridin-4-ylethyl)pyridine-2- carboxamide 495.6372 881

4-[(1-methyl-2-{[2-(methyl- oxy)phenyl]amino}-1H-benz-imidazol-5-yl)oxy]-N-[3-(4- methylpiperazin-1-yl)propyl]-pyridine-2-carboxamide 530.6 372 882

4-[(1-methyl-2-{[2-(methyloxy)- phenyl]amino}-1H-benz-imidazol-5-yl)oxy]-N-(3- morpholin-4-ylpropyl)pyridine- 2-carboxamide517.6 372 883

N-methyl-4-[(1-methyl-2-{[2- (methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2- pyridin-4-ylethyl)pyridine-2- carboxamide509.6 372 884

N-[(1-ethylpyrrolidin-2-yl)- methyl]-4-[(1-methyl-2-{[2-(methyloxy)phenyl]amino}-1H- benzimidazol-5-yl)oxy]pyridine-2-carboxamide 501.6 372 885

4-[(1-methyl-2-{[2-(methyl- oxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N- (1,2,2,6,6-pentamethylpiperidin-4-yl)pyridine-2-carboxamide 543.7 372 886

N-methyl-4-[(1-methyl-2-{[2- (methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-[2- (methyloxy)ethyl]pyridine-2- carboxamide462.5 372 887

4-[(1-methyl-2-{[2-(methyl- oxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2- morpholin-4-ylethyl)pyridine-2- carboxamide503.6 372 888

N-methyl-4-[(1-methyl-2-{[2- (methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N- propylpyridine-2-carboxamide 446.5 372 889

N-methyl-4-[(1-methyl-2-{[2- (methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(1- methylpiperidin-4-yl)pyridine-2-carboxamide 501.6 372 890

N-[2-(dimethylamino)ethyl]-N- methyl-4-[(1-methyl-2-{[2-(methyloxy)phenyl]amino}-1H- benzimidazol-5-yl)oxy]pyridine-2-carboxamide 475.6 372 891

5-{[2-(1H-benzimidazol-2- yl)pyridin-4-yl]oxy}-1-methyl-N-[2-(methyloxy)phenyl]-1H- benzimidazol-2-amine 463.5 372 892

5-{[2-(1H-benzimidazol-2- yl)pyridin-4-yl]oxy}-N-(2-fluorophenyl)-1-methyl-1H- benzimidazol-2-amine 451.5 372 893

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(1H-imidazol-4- yl)ethyl]pyridine-2-carboxamide 472.5 372894

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(1-methyl- pyrrolidin-2-yl)ethyl]pyridine-2- carboxamide489.6 372 895

N-[2-(dimethylamino)ethyl]-4- ({2-[(4-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}- oxy)pyridine-2-carboxamide 449.6 372 896

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(1H-indol-3-yl)- ethyl]pyridine-2-carboxamide 521.6 372 897

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(methyloxy)- propyl]pyridine-2-carboxamide 450.5 372 898

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(methyloxy)- ethyl]pyridine-2-carboxamide 436.5 372 899

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-pyridin-4-ylethyl)- pyridine-2-carboxamide 483.6 372 900

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(4-methyl- piperazin-1-yl)propyl]pyridine- 2-carboxamide518.6 372 901

5-{[2-({(2R,5R)-2-[(dimethyl- amino)methyl]-5-methyl-morpholin-4-yl}carbonyl)- pyridin-4-yl]oxy}-N-(4-fluoro-phenyl)-1-methyl-1H-benz- imidazol-2-amine 519.6 372 902

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(3-morpholin-4-yl- propyl)pyridine-2-carboxamide 505.6 372 903

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-(2-pyridin- 4-ylethyl)pyridine-2-carbox- amide 497.6372 904

N-[(1-ethylpyrrolidin-2-yl)- methyl]-4-({2-[(4-fluoro-phenyl)amino]-1-methyl-1H- benzimidazol-5-yl}oxy)-pyridine-2-carboxamide 489.6 372 905

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(1,2,2,6,6-penta- methylpiperidin-4-yl)pyridine-2- carboxamide531.7 372 906

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-[2-(methyl- oxy)ethyl]pyridine-2-carbox- amide 450.6372 907

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-morpholin-4-yl- ethyl)pyridine-2-carboxamide 491.6 372 908

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-propylpyridine-2- carboxamide 434.6 372 909

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-(1-methyl- piperidin-4-yl)pyridine-2- carboxamide489.6 372 910

N-[2-(dimethylamino)ethyl]-4- ({2-[(4-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}- oxy)-N-methylpyridine-2- carboxamide 463.6372 911

5-{[2-({(2R,5S)-2-[(dimethyl- amino)methyl]-5-methyl-morpholin-4-yl}carbonyl)- pyridin-4-yl]oxy}-N-(4-fluoro-phenyl)-1-methyl-1H-benz- imidazol-2-amine 519.6 372 912

5-{[2-(1H-benzimidazol-2-yl)- pyridin-4-yl]oxy}-N-(4-fluoro-phenyl)-1-methyl-1H-benz- imidazol-2-amine 451.5 821 913

4-({2-[(4-bromo-2-fluoro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 471.3 120a 914

4-({2-[(4-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-phenylethyl)- pyridine-2-carboxamide 499.0 372 915

4-({2-[(4-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-{2-[2-(methyloxy)- phenyl]ethyl}pyridine-2-carbox- amide 529.0372 916

4-({2-[(4-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(dimethylamino)- ethyl]pyridine-2-carboxamide 466.0 372 917

4-({2-[(4-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-pyridin-4-ylethyl)- pyridine-2-carboxamide 500.0 372 918

N-(4-chlorophenyl)-5-{[2- ({(2R,5R)-2-[(dimethylamino)-methyl]-5-methylmorpholin-4- yl}carbonyl)pyridin-4-yl]oxy}-1-methyl-1H-benzimidazol-2- amine 536.0 372 919

4-({2-[(4-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-(2-pyridin- 4-ylethyl)pyridine-2- carboxamide 514.0372 920

4-({2-[(4-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(1,2,2,6,6-penta- methylpiperidin-4-yl)pyridine-2- carboxamide548.1 372 921

4-({2-[(4-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-propyl- pyridine-2-carboxamide 450.9 372 922

4-({2-[(4-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-(1-methyl- piperidin-4-yl)pyridine-2- carboxamide506.0 372 923

4-({2-[(4-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(dimethylamino)- ethyl]-N-methylpyridine-2- carboxamide480.0 372 924

N-(4-chlorophenyl)-5-{[2- ({(2R,5S)-2-[(dimethylamino)-methyl]-5-methylmorpholin-4- yl}carbonyl)pyridin-4-yl]oxy}-1-methyl-1H-benzimidazol-2- amine 536.0 372 925

4-({2-[(4-chlorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-N-[2-(methyl- oxy)ethyl]pyridine-2-carbox- amide 466.9372 926

N-(4-fluorophenyl)-5-{[2-(3H- imidazo[4,5-b]pyridin-2-yl)-pyridin-4-yl]oxy}-1-methyl-1H- benzimidazol-2-amine 452.5 821 927

N-(4-fluorophenyl)-1-methyl-5- {[2-(1H-naphtho[2,3-d]-imidazol-2-yl)pyridin-4-yl]oxy}- 1H-benzimidazol-2-amine 501.5 821 928

N-(4-fluorophenyl)-1-methyl-5- {[2-(5-methyl-1H-benzimidazol-2-yl)pyridin-4-yl]oxy}-1H- benzimidazol-2-amine 465.5 821 929

N-(4-fluorophenyl)-1-methyl-5- ({2-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]pyridin-4- yl}oxy)-1H-benzimidazol-2- amine 549.6821 930

N-(4-fluorophenyl)-1-methyl-5- {[2-(1-methyl-1H-benzimidazol-2-yl)pyridin-4-yl]oxy}-1H- benzimidazol-2-amine 465.5 821 931

5-({2-[5-(1,1-dimethylethyl)- 1H-benzimidazol-2-yl]pyridin-4-yl}oxy)-N-(4-fluorophenyl)-1- methyl-1H-benzimidazol-2- amine 507.6 821932

N-[(1-ethylpyrrolidin-2-yl)- methyl]-4-[(1-methyl-2-{[3-(trifluoromethyl)phenyl]amino}- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 539.3 372 933

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2- morpholin-4-ylethyl)pyridine-2- carboxamide541.3 372 934

N-[3-(4-methylpiperazin-1-yl)- propyl]-4-[(1-methyl-2-{[3-(tri-fluoromethyl)phenyl]amino}- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 568.4 372 935

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-1,3- thiazol-2-ylpyridine-2-carbox- amide 511.2372 936

N-[2-(1-methylpyrrolidin-2-yl)- ethyl]-4-[(1-methyl-2-{[3-(tri-fluoromethyl)phenyl]amino}- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 539.3 372 937

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-[2-(2- oxoimidazolidin-1-yl)ethyl]-pyridine-2-carboxamide 540.3 372 938

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2- pyrrolidin-1-ylethyl)pyridine-2-carboxamide 525.3 372 939

N-[3-(1H-imidazol-1-yl)propyl]- 4-[(1-methyl-2-{[3-(trifluoro-methyl)phenyl]amino}-1H- benzimidazol-5-yl)oxy]pyridine- 2-carboxamide536.3 372 940

N-[2-(methyloxy)ethyl]-4-[(1- methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 486.3372 941

N-(2-hydroxyethyl)-4-[(1- methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 472.2372 942

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2- piperidin-1-ylethyl)pyridine-2- carboxamide539.3 372 943

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(3- piperidin-1-ylpropyl)pyridine-2-carboxamide 553.3 372 944

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(3- pyrrolidin-1-ylpropyl)pyridine-2-carboxamide 539.3 372 945

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2- pyridin-4-ylethyl)pyridine-2- carboxamide533.3 372 946

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2- piperazin-1-ylethyl)pyridine-2- carboxamide540.2 372 947

N-[3-(methyloxy)propyl]-4-[(1- methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 500.2372 948

N-[2-(acetylamino)ethyl]-4-[(1- methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2- carboxamide 513.3372 949

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N- pyrrolidin-3-ylpyridine-2- carboxamide 497.2372 950

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-[3-(2- oxopyrrolidin-1-yl)propyl]-pyridine-2-carboxamide 470.3 372 951

4-[(1-methyl-2-{[3-(trifluoro- methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N- propylpyridine-2-carboxamide 456.2 372 952

N-ethyl-4-[(1-methyl-2-{[3- (trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 456.2 372 953

5-{[2-(1H-benzimidazol-2- yl)pyridin-4-yl]oxy}-1-methyl-N-[3-(trifluoromethyl)phenyl]- 1H-benzimidazol-2-amine 501.2 821 954

5-{[2-(1H-benzimidazol-2- yl)pyridin-4-yl]oxy}-1-methyl-N-[3-(1-methylethyl)phenyl]- 1H-benzimidazol-2-amine abran 821 955

1-methyl-5-{[2-(5-methyl-1H- benzimidazol-2-yl)pyridin-4-yl]oxy}-N-[3-(trifluoromethyl)- phenyl]-1H-benzimidazol-2- amine 515.2821 956

1-methyl-5-{[2-(1H- naphtho[2,3-d]imidazol-2-yl)-pyridin-4-yl]oxy}-N-[3-(tri- fluoromethyl)phenyl]-1H-benzimidazol-2-amine 551.3 821 957

1-methyl-5-{[2-(1-methyl-1H- benzimidazol-2-yl)pyridin-4-yl]oxy}-N-[3-(trifluoromethyl)- phenyl]-1H-benzimidazol-2- amine 515.2821 958

(2-{4-[(1-methyl-2-{[3- (trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]- pyridin-2-yl}-1H-benzimidazol-5-yl)(phenyl)methanone 605.2 821 959

5-{[2-(5-bromo-1H- benzimidazol-2-yl)pyridin-4- yl]oxy}-1-methyl-N-[3-(trifluoromethyl)phenyl]-1H- benzimidazol-2-amine 579.1 821 960

5-{[2-(5-chloro-6-fluoro-1H- benzimidazol-2-yl)pyridin-4-yl]oxy}-1-methyl-N-[3- (trifluoromethyl)phenyl]-1H- benzimidazol-2-amine553.2 821 961

5-{[2-(5-chloro-1H- benzimidazol-2-yl)pyridin-4- yl]oxy}-1-methyl-N-[3-(trifluoromethyl)phenyl]-1H- benzimidazol-2-amine 535.2 821 962

5-{[2-(5-fluoro-1H- benzimidazol-2-yl)pyridin-4- yl]oxy}-1-methyl-N-[3-(trifluoromethyl)phenyl]-1H- benzimidazol-2-amine 519.4 821 963

1-methyl-5-({2-[5- (trifluoromethyl)-1H- benzimidazol-2-yl]pyridin-4-yl}oxy)-N-[3 - (trifluoromethyl)phenyl]-1H- benzimidazol-2-amine 569.2821 964

methyl 2-{4-[(1-methyl-2-{[3- (trifluoromethyl)phenyl]amino}-1H-benzimidazol-5- yl)oxy]pyridin-2-yl}-1H- benzimidazole-5-carboxylate559.2 821 965

5-{[2-(5,6-dichloro-1H- benzimidazol-2-yl)pyridin-4-yl]oxy}-1-methyl-N-[3- (trifluoromethyl)phenyl]-1H- benzimidazol-2-amine569.1 821 966

5-({2-[5-(1,1-dimethylethyl)- 1H-benzimidazol-2-yl]pyridin-4-yl}oxy)-1-methyl-N-[3- (trifluoromethyl)phenyl]-1H- benzimidazol-2-amine557.3 821 967

1-methyl-5-{[2-(3-phenyl-1,2,4- oxadiazol-5-yl)pyridin-4- yl]oxy}-N-[3-(trifluoromethyl)phenyl]-1H- benzimidazol-2-amine 529.2 821 968

5-({2-[7-fluoro-6-(4-methyl- piperazin-1-yl)-1H-benzimidazol-2-yl]pyridin-4- yl}oxy)-1-methyl-N-[3-(1-methylethyl)phenyl]-1H- benzimidazol-2-amine 591.3 821 969

1-methyl-N-[3-(1-methyl- ethyl)phenyl]-5-[(2-{5-[(3-pyrrolidin-1-ylpropyl)oxy]-1H- benzimidazol-2-yl}pyridin-4-yl)oxy]-1H-benzimidazol-2- amine 602.7 821 970

N-(2-hydroxyethyl)-4-{[1- methyl-2-({3-[(trifluoromethyl)-thio]phenyl}amino)-1H- benzimidazol-5-yl]oxy}- pyridine-2-carboxamide504.1 820 971

N-(2-hydroxyethyl)-4-{[1- methyl-2-({4-[(trifluoromethyl)-thio]phenyl}amino)-1H- benzimidazol-5-yl]oxy}- pyridine-2-carboxamide504.1 820 972

4-({2-[(3-fluoro-4-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2- hydroxyethyl)pyridine-2- carboxamide 436.2820 973

4-({2-[(4-bromo-3-chloro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2- hydroxyethyl)pyridine-2- carboxamide 516820 974

4-({2-[(4-chloro-3-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2- hydroxyethyl)pyridine-2- carboxamide 452.2820 975

4-({2-[(4-fluorophenyl)amino]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-hydroxyethyl)- pyridine-2-carboxamide 422.2 820 976

4-({2-[(3-chloro-4-fluoro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2- hydroxyethyl)pyridine-2- carboxamide 456.2820 977

N-(2-hydroxyethyl)-4-[(1- methyl-2-{[4-methyl-3-(trifluoromethyl)phenyl]amino}- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 486.2 820 978

4-({2-[(3-chloro-4-methyl- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2- hydroxyethyl)pyridine-2- carboxamide 452.2820 979

4-({2-[(4-bromo-3-fluoro- phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2- hydroxyethyl)pyridine-2-carbox- amide 502.1820 980

5-({2-[4-fluoro-5-(4-methyl- piperazin-1-yl)-1H-benz-imidazol-2-yl]pyridin-4-yl}oxy)- 1-methyl-N-[3-(trifluoromethyl)-phenyl]-1H-benzimidazol-2- amine 428.2 821 981

5-{[2-(1H-benzimidazol-2-yl)- pyridin-4-yl]oxy}-N-(4-chloro-3-pyridin-4-ylphenyl)-1-methyl- 1H-benzimidazol-2-amine 545.0 821 982

1-methyl-5-{[2-(5-{[2-(methyl- oxy)ethyl]oxy}-1H-benz-imidazol-2-yl)pyridin-4-yl]oxy}- N-{3-[(trifluoromethyl)thio]-phenyl}-1H-benzimidazol-2- amine 607.2 821 983

5-({2-[5-(4-cyclopentyl- piperazin-1-yl)-1H-benz-imidazol-2-yl]pyridin-4-yl}oxy)- 1-methyl-N-{3-[(trifluoro-methyl)thio]phenyl}-1H- benzimidazol-2-amine 685.3 821 984

1-methyl-N-(3-pyridin-4-yl- phenyl)-5-({2-[5-(trifluoro-methyl)-1H-benzimidazol-2- yl]pyridin-4-yl}oxy)-1H- benzimidazol-2-amine578.3 821

EXAMPLE 985 Synthesis of Oxime Series:4-[2-(4-Bromo-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxyl-pyridine-2-carbaldehydeoxime

[0461] Step 1. Synthesis of[4-(4-Methylamino-3-nitro-phenoxy)-pyridin-2-yl]-methanol

[0462] A flame dried 500 mL three-necked round bottom flask purged withN₂ was charged with LAH (2.32 g, 58.0 mmol) and dry THF (60 mL). Theresulting suspension was cooled to 0° C. and a suspension of t-butylester 1 (10.0 g, 29.0 mmol) in dry THF (60 mL) was slowly added whilekeeping the internal reaction temperature under 5° C. The reaction wasstirred at 0° C. for 30 min then at rt for 30 min. After the reactionwas judged complete, the mixture was treated with successive dropwiseaddition of water (2.3 mL), 10% NaOH (253 mL), and water (7.2 mL). Theresulting suspension was filtered through Celite, washed with ethylacetate and methanol, and the collected organics concentrated. The crudeproduct was absorbed onto silica gel and purified by flashchromatography (97: 3 CH₂Cl₂/MeOH) to give 2 as an orange solid: ¹H NMR(300 MHz, CDCl₃) δ 8.40 (d, J=,5.5 Hz, 1 H), 8.05 (br s, 1H), 7.96 (d,J=2.75 Hz, 1 H), 7.29 (d, J=2.75 Hz, 1 H), 6.92 (d, J=9.35 Hz, 1 H),6.75 (m, 2 H), 4.68 (s, 2 H), 3.07 (d, J=5.23 Hz, 3 H).

[0463] Step 2. Synthesis of4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carbaldehyde

[0464] A 250 mL reaction tube was charged with benzyl alcohol 1 (1.0 g,3.6 mmol), MnO₂ (4.7 g, 54 mmol) and EtOAc (20 mL). The reaction tubewas sealed was heated to 120 ° C. with stirring for 2 h. The reactionwas allowed to cool to rt, then filtered through Celite and washedsuccessively with EtOAc, MeOH, and EtOH. The combine organics wereconcentrated to give 936 mg (3.4 mmol, 94%) of 2 as an orange solid: ¹HNMR (300 MHz, CDCl₃) δ 10.01 (s, 1 H), 8.64 (d, J =5.5 Hz, 1 H), 8.09(br s, 1 H), 7.96 (d, J=2.75 Hz, 1 H), 7.37 (d, J=2.48 Hz, 1 H), 7.29(d, J=2.75 Hz, 1 H), 7.08 (dd, J=2.47, 5.5 Hz, 1 H), 6.94 (d, J =9.35Hz, 1 H), 3.08 (d, J =5.23 Hz, 3 H).

[0465] Step 3. Synthesis of4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carbaldehyde oxime

[0466] A 50 mL round bottom flask was charged with 1 (680 mg, 2.5 mmol),hydroxylamine HCl (191 mg, 2.75 mmol), pyridine (0.25 mL, 3.0 mmol) andethanol (10 mL). The resulting reaction mixture was stirred at rtovernight. The crude product was concentrated, absorbed onto silica gel,and purified by flash chromatography (97:3 CH₂Cl₂/MeOH to give 2 as anorange solid. LCMS m/z 289.2 (MH⁺), t_(R)=2.06 min.

[0467] Step 4. Synthesis of4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carbaldehyde oxime

[0468] A reaction tube was charged with suspension of 1 (330 mg, 1.15mmol) and Lindlar catalyst (245 mg, 10 mol %) in methanol (5 mL),sealed, and placed on a Parr shaker. The reaction was pressurized withH₂ (60 psi) and maintained for 1 h. The reaction was filtered throughCelite and the remaining solids were washed with MeOH. The combinedorganics were concentrated to give 2 as a brown semi-solid which wastaken on without further purification.

[0469] Step 5. Synthesis of4-[2-(4-Bromo-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carbaldehydeoxime

[0470] A 5 mL round bottom flask was charged with4-bromophenylisothiocyanate (54 mg, 0.25 mmol), diamine 1 (65 mg, 0.25mmol), and MeOH (1 mL). The resulting reaction was maintained at rtovernight. Methyl iodide (20 μL, 0.33 mmol) was added to the reactionand stirred overnight. The reaction was concentrated and the resultingresidue was purified by reverse-phase HPLC. LCMS m/z 438.1 (MH⁺),t_(R)=1.87 min.

EXAMPLE 986 Synthesis of O-methyl-oxime Series:4-[1-Methyl-2-(4-trifluoromethylsulfanyl-phenylamino)-1H-benzoimidazol-5-yloxy]-pyridine-2-carbaldehydeO-methyl-oxime

[0471] Step 1. Synthesis of4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carbaldehyde O-methyl-oxime

[0472] A 25 mL round bottom flask was charged with a suspension of 1(600 mg, 2.2 mmol), methoxyamine HCl (202 mg, 2.42 mmol), and pyridine(0.22 mL, 2.6 mmol) in ethanol (9 mL). The resulting reaction mixturewas stirred at rt overnight. The crude 5 product was concentrated,absorbed onto silica gel, and purified by flash chromatography (97:3CH₂Cl₂/MeOH) to give 2 as an orange solid. LCMS m/z 303.2 (MH⁺),t_(R)=2.40 min.

[0473] Step 2. Synthesis of4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carbaldehyde O-methyl-oxime

[0474] A reaction tube was charged with a suspension of 1 (270 mg, 0.9mmol) and Lindlar catalyst (192 mg, 10 mol %) in methanol (5 mL), andwasthen placed on a Parr shaker. The was reaction pressurized with H₂(60 psi) and maintained for 1 h. The reaction was filtered throughCelite and the remained solids were washed with methanol. The combinedorganics were concentrated to give 2 as a brown semi-solid which wascarried forward without further purification LCMS m/z 273.3 (MH⁺),t_(R)=1.56 min.

[0475] Step 3. Synthesis of4-[1-Methyl-2-(4-trifluoromethylsulfanyl-phenylamino)-1H-benzoimidazol-5-yloxy]-pyridine-2-carbaldehydeO-methyl-oxime

[0476] A 5 mL round bottom flask was charged with4-trifluoromethylthio-phenylisothiocyanate (24 mg, 0.1 mmol), diamine 1(27 mg, 0.1 mmol), and MeOH (0.5 mL). The reaction was maintained at rtovernight, after which methyl iodide (8 μL, 0.13 mmol) was added. After16 h, the reaction was concentrated and the resulting residue waspurified by reverse-phase HPLC. LCMS m/z 474.3 (MH⁺), t_(R)=2.42 min.

EXAMPLE 987

[0477]

[0478] Synthesized as described in Example 986 step 3 using4-bromophenyl isothiocyanate. LCMS m/z 402.4 (MH⁺), t_(R)=2.15 min.

EXAMPLE 988

[0479]

[0480] Synthesized as described in Example 986 step 3 using4-ethylphenylisiothiocyanate. LCMS m/z 402.4 (MH⁺), t_(R)=2.15 min.

EXAMPLE 989

[0481]

[0482] Synthesized as described in Example 986 step 3 using4-bromo-2-trifluoro-methoxyphenylisothiocyanate. LCMS m/z 536.2 (MH⁺),t_(R)=2.38 min.

EXAMPLE 990

[0483]

[0484] Synthesized as described in Example 986 step 3 using2,4-dimethylphenylisothiocyanate. LCMS m/z 402, (MH⁺), t_(R)=2.07 min.

EXAMPLE 991 Synthesis of Benzyl Alcohol Series:{4-[2-(4-Chloro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-yl}-methanol

[0485] Step 1. Synthesis of[4-(3-Amino-4-methylamino-phenoxy)-pyridin-2-yl]-methanol

[0486] A suspension of nitroaniline 1 (550 mg, 2.0 mmol) in methanol wassparged with N₂ for 20 min after which 10% Pd/C (106 mg, 0.1 mmol) wasadded. The reaction was charged with H₂ and maintained under a H₂atmosphere overnight at rt. The reaction was sparged with N₂ andfiltered through Celite. The collected solids were washed with EtOAc(3×50 mL), and the combined organic layers were dried (MgSO₄) andconcentrated to afford 2, which was taken on without furtherpurification.

[0487] Step 2. Synthesis of{4-[2-(4-Chloro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-yl}-methanol.

[0488] A 5 mL round bottom flask was charged with4-chlorophenylisothiocyanate (34 g, 0.2 mmol), diamine 1 (49 mg, 0.2mmol), and MeOH (1 mL) and the resulting reaction was maintained at rtovernight. Ferric chloride (16 mg, 0.1 mmol) was added and the redreaction mixture was stirred overnight. The reaction was partitionedwith EtOAc and water, the layers were separated and the aqueous phasewas neutralized (pH=7) with saturated aqueous Na₂CO₃ solution. Theaqueous phase was extracted with EtOAc. The combined organic layers werewashed with brine, dried, and concentrated to give a brown solid. Thereaction was concentrated and the resulting residue purified onreverse-phase HPLC. LCMS m/z 381.3 (MH⁺), t_(R)=2.27 min.

EXAMPLE 992

[0489]

[0490] Synthesized as described in Example 1058 step 2 using4-fluorophenylisiothiocyanate. LCMS m/z 365.4 (MH⁺), t_(R)=2.04 min.

EXAMPLE 993

[0491]

[0492] Synthesized as described in Example 991 step 2 using4-bromo-3-methylphenylisiothiocyanate. LCMS m/z 439.3 (MH⁺), t_(R)=2.79min.

EXAMPLE 994

[0493]

[0494] Synthesized as described in Example 991 step 2 using4-bromo-2-trifluoromethoxyphenylisothiocyanate. LCMS m/z 511.3 (MH⁺),t_(R)=3.08 min.

EXAMPLE 995

[0495]

[0496] Synthesized as described in Example 991 step 2 using4-methylthiophenylisiothiocyanate. LCMS m/z 393.4 (MH⁺), t_(R)=2.46 min.

EXAMPLE 995

[0497]

[0498] Synthesized as described in Example 991 step 2 using3-ethylphenylisiothiocyanate. LCMS m/z 375.4 (MH⁺), t_(R)=2.57 min.

EXAMPLE 996

[0499]

[0500] Synthesized as described in Example 991 step 2 using4-trifluoromethylthio-phenylisiothiocyanate. LCMS m/z 447.3 (MH⁺),t_(R)=3.21 min.

EXAMPLE 997

[0501]

[0502] Synthesized as described in Example 991 step 2 using3-iodophenylisiothiocyanate. LCMS m/z 473.2 (MH⁺), t_(R)=2.57 min.

EXAMPLE 998

[0503]

[0504] Synthesized as described in Example 991 step 2 using3-trifluoromethylthiophenylisothiocyanate. LCMS m/z 447.3 (MH⁺),t_(R)=3.08 min.

EXAMPLE 9994-[2-(4-Bromo-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid phenylamide. Procedure for Synthesis of Anilide Series (4-Br and3-iPr West-Ends)

[0505] Synthesis of4-[2-(4-Bromo-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid phenylamide.

[0506] A suspension of 1 (44 mg, 0.1 mmol), HBTU (46 mg, 0.12 mmol), andDIEA (43 μL, 0.25 mmol) in NMP (0.5 mL) was shaken for 30 min at rt.Aniline was added and the reaction was shaken overnight. The crudeproduct purified on reverse-phase HPLC. LCMS m/z 515.2 (MH⁺), t_(R)=2.75min.

[0507] Synthesized as described in Example 999 using N,O-dimethylhydroxylamine HCl. LCMS m/z 483.3 (MH⁺), t_(R)=2.07 min.

[0508] Synthesized as described in Example 999 using 4-bromoaniline.LCMS m/z 594.0 (MH⁺), t_(R)=5.39 min.

[0509] Synthesized as described in Example 999 using3,4-dimethylaniline. LCMS m/z 543.2 (MH⁺), t_(R)=5.39 min.

[0510] Synthesized as described in Example 999 using3-trifluoromethylaniline. LCMS m/z 583.1 (MH⁺), t_(R)=3.12 min.

[0511] Synthesized as described in Example 999 using 3-chloroaniline.LCMS m/z 550.1 (MH⁺), t_(R)=5.28 min.

[0512] Synthesized as described in Example 999 using 3-ethylaniline.LCMS m/z 543.2 (MH⁺), t_(R)=3.16 min.

[0513] Synthesized as described in Example 1067 using 4-methylaniline.LCMS m/z 529.2 (MH⁺), t_(R)=5.15 min.

[0514] Synthesized as described in Example 999 using 3-isopropylaniline.LCMS m/z 520.3 (MH⁺), t_(R)=5.98 min.

[0515] Synthesized as described in Example 999 using3-tert-butylaniline. LCMS m/z 534.3 (MH⁺), t_(R)=3.32 min.

[0516] Synthesized as described in Example 999 using3-trifluoromethoxyaniline. LCMS m/z 562.2 (MH⁺), t_(R)=3.15 min.

[0517] Synthesized as described in Example 999 using 3-biphenylamine.LCMS m/z 554.3 (MH⁺), t_(R)=3.28 min.

[0518] Synthesized as described in Example 999 using 4-bromoaniline.LCMS m/z 557.2 (MH⁺), t_(R)=5.65 min.

[0519] Synthesized as described in Example 999 using3-trifluoromethylaniline. LCMS m/z 546.3 (MH⁺), t_(R)=5.74 min.

[0520] Synthesized as described above in Example 999 using3-iodoaniline. LCMS m/z 604.2 (MH⁺), t_(R)=5.81 min.

EXAMPLE 10144-[1-Methyl-2-(3-phenoxy-phenylamino)-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid methylamide

[0521] Step 1. Synthesis of 3-phenoxyphenylisothiocyanate

[0522] To a stirring solution of 3-phenoxyaniline (185 mg, 1.0 mmol) inacetone (4.0 mL) at 0° C. was added thiophosgene (0.23 mL, 3.0 mmol) andthe resulting reaction maintained for 30 min. The reaction determinedcomplete by TLC (4:1 hexane/EtOAc). The reaction was concentrated,azeotroped with toluene and taken on without further purification.

[0523] Step 2. Synthesis of4-[1-Methyl-2-(3-phenoxy-phenylamino)-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid methylamide

[0524] A 1 dram vial was charged with a solution of3-phenoxyphenylisothiocyanate (23 mg, 0.1 mmol), diamine 1 (27 mg, 0.1mmol), and MeOH (0.5 mL) and the reaction was shaken at rt overnight.Methyl iodide (8 μL, 0.13 mmol) was added and the mixture shakenovernight. The reaction was concentrated and the resulting residuepurified on reverse phase HPLC. LCMS m/z 466.3 (MH³⁰ ), t_(R)=2.40 min.

[0525] Synthesized as described in Example 1014 step 2 using4-trifluoromethylthiophenylisothiocyanate. LCMS m/z 474.5 (MH³⁰ ),t_(R)=3.76 min.

[0526] Synthesized as described in Example 1014 step 2 using3-trifluoromethylthiophenylisothiocyanate. LCMS m/z 474.5 (MH³⁰ ),t_(R)=3.65 min.

[0527] Synthesized as described in Example 1014 step 2 using4-1-isothiocyanato-4-methanesulfonyl-benzene, prepared as in step 1.LCMS m/z 452.5 (MH³⁰ ), t_(R)=2.86 min.

[0528] Synthesized as described in Example 1014 step 2 using4-(2-isothiocyanato-4-trifluoromethyl-phenoxy)-benzonitrile, prepared asin step 1. LCMS m/z 559.6 (MH³⁰ ), t_(R)=4.22 min.

[0529] Synthesized as described in Example 1014 step 2 using2-(2-methoxy-phenoxy)-5-trifluoromethyl-phenylisothiocyanate, preparedas in step 1. LCMS m/z 564.6 (MH³⁰ ), t_(R)=4.42 min.

[0530] Synthesized as described in Example 1014 step 2 using2-phenylsulfanyl-phenylisothiocyanate, prepared as in step 1. LCMS m/z482.5 (MH³⁰ ), t_(R)=3.85 min.

[0531] Synthesized as described in Example 1014 step 2 using4-isothiocyanato-3-trifluoromethoxy-benzonitrile, prepared as in step 1.LCMS m/z 483.4 (MH³⁰ ), t_(R)=2.35 min.

[0532] Synthesized as described in Example 1014 step 2 using2,4-dibromo-6-fluorophenylisothiocyanate. LCMS m/z 550.3 (MH³⁰ ),t_(R)=3.50 min.

[0533] Synthesized as described in Example 1014 step 2 using4-bromo-2-trifluoromethoxy-phenylisothiocyanate. LCMS m/z 537.3 (MH³⁰ ),t_(R)=3.89 min.

[0534] Synthesized as described in Example 1014 step 2 usingphenylisothiocyanate. LCMS m/z 374.5 (MH³⁰ ), t_(R)=2.84 min.

[0535] Synthesized as described in Example 1014 step 2 using2-phenoxy-phenylisothiocyanate, prepared as in step 1. LCMS m/z 466.5(MH³⁰ ), t_(R)=2.37 min.

[0536] Synthesized as described in Example 1014 step 2 using2-methyl-phenylisothiocyanate. LCMS m/z 388.5 (MH³⁰ ), t_(R)=2.99 min.

[0537] Synthesized as described in Example 1014 step 2 using2-difluoromethoxy-phenylisothiocyanate. LCMS m/z 440.5 (MH³⁰ ),t_(R)=3.13 min.

[0538] Synthesized as described in Example 1014 step 2 using2-iodo-phenylisothiocyanate. LCMS m/z 500.4 (MH³⁰ ), t_(R)=2.07 min.

[0539] Synthesized as described in Example 1014 step 2 using2,6-diisopropyl-phenylisothiocyanate. LCMS m/z 430.5 (MH³⁰ ), t_(R)=2.27min.

EXAMPLE 1030.4-[2-(4-Bromophenyl)-1-methyl-1H-benzimidazol-5-yloxy]-pyridine-2-carboxylicacid methylamide.

[0540]

[0541] A mixture of diamine 1 (137 mg, 0.36 mmol) and4-bromobenzaldehyde (66 mg, 0.50 mmol) in dry dioxane (2 mL) was heatedto 100° C. for 16 h. The reaction mixture was allowed to cool to rt andwas then concentrated. The resulting residue was purified by reversephase HPLC to furnish 2 as the TFA salt: LCMS m/z 437.1, t_(R)=2.16 min.

EXAMPLE 10314-[1-Methyl-2-(4-methylbenzylamino)-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid methylamide.

[0542]

[0543] Prepared as per Example 120b using 4-methylbenzyl thioisocyanate:LCMS m/z 402.2 (MH³⁰ ), t_(R)=1.91 min.

EXAMPLE 10324-[2-(4-Bromophenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide.

[0544]

[0545] Prepared as per Example 371 usingamido-1-(3-aminopropyl)pyrrolidine: LCMS m/z 549.5 (MH³⁰ ), t_(R)=2.97min.

EXAMPLE 1033(4-Bromophenyl)-[1-methyl-5-(pyridin-4-yloxy)-1H-benzolimidazol-2-yl]-amine

[0546]

[0547] A solution of acid 1 (44 mg, 0.1 mmol) in dry NMP (1 mL) washeated at 200° C. for 20 min. The reaction was allowed to cool to rt andthe crude reaction mixture was directly purified on reverse-phase HPLCto provide 2 as a TFA salt: ¹H NMR(300 MHz, CD3OD) δ 8.67 (d, J=7.4 Hz,2 H), 7.70 (d, J=8.5 Hz, 1 H), 7.68 (d, J=8.8 Hz, 2 H), 7.45 (d, J=8.8Hz, 2 H), 7.42 (d, J=7.4 Hz, 2 H), 7.32 (d, J=2.2 Hz, 1 H), 7.26 (dd,J=2.2, 8.5 Hz, 1 H), 3.86 (s, 3 H); LCMS m/z 395.0 (MH³⁰ ), t_(R)=1.48min.

[0548] LCMS m/z 359.3 (MH³⁰ ), t_(R)=1.91 min.

EXAMPLE 1035{4-[2-(4-Bromophenylamino)-1-methyl-1H-benzolimidazol-5-yloxy]-pyridin-2-yl}-methanol

[0549]

[0550] A suspension of t-butyl ester 1 (496 mg, 1.0 mmol) in dry THF (3mL) was added to a stirring suspension of LAH (61 mg, 1.6 mmol) in dryTHF (2 mL) at −78° C. The reaction was allowed to warm to rt over 3 h.After the reaction was judged complete by LCMS, water (30 μl, 1.7 mmol)and NaF (270 mg, 6.4 mmol) were added and the resulting mixture wasstirred vigorously overnight at rt. The crude mixture was filteredthrough Celite and the remaining solids were rinsed with EtOAc. Thecombined organic portions were concentrated and a portion of theresulting residue was purified by reverse-phase HPLC to furnish alcohol2 as a TFA salt: ¹H NMR (300 MHz, CD3OD) δ 8.56 (d, J=7.2 Hz, 1 H), 7.72(d, J=8.5 Hz, 1 H), 7.69 (d, J=8.8 Hz, 2 H), 7.45 (d, J=8.8 Hz, 2 H),7.33 (m, 3 H), 7.28 (dd, J=2.2, 8.5 Hz, 1 H), 4.86 (app s, 2 H), 3.87(s, 3 H); LCMS m/z 425.1, t_(R)=1.49 min.

EXAMPLE 1036(4-Bromophenyl)-[1-methyl-5-(2-methylaminomethyl-pyridin-4-yloxy)-1Hbenzoimidazol-2-yl]-amine General Preparation for Benzyl Amines

[0551] Step 1.4-[2-(4-Bromophenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxaldehyde

[0552] Dry DMSO (0.1 mL, 1.4 mmol) was added to a solution of oxalylchloride (0.11 mL, 1.3 mmol) in dry THF (2 mL) at −78 ° C. and theresulting solution was maintained at −78° C. for 30 min. A solution ofalcohol 1 in dry THF (2 mL) was then introduced and the resultingreaction was maintained at −78° C. for 30 min, then at −50° C. for 45min. Triethylamine (0.5 mL, 3.6 mmol) was added and the reaction wasallowed to warm to rt over 1 h. The reaction was quenched with water andpartitioned with EtOAc. The layers were separated and the aqueousportion was extracted with EtOAc (3×). The combined organic phases werewashed with brine, dried (MgSO₄), and concentrated. The resultingresidue was carried forward without further purification.

[0553] Step 2.(4-Bromophenyl)-[1-methyl-5-(2-methylaminomethyl-pyridin-4-yloxy)-1Hbenzoimidazol-2-yl]-amine.

[0554] Methyl amine (0.3 mL, 0.6 mmol, 2.0 M in MeOH) was added to asolution of aldehyde 1 in MeOH (1 mL) and the reaction was maintained atrt for 2 d. The reaction was acidified by addition of acetic acid(pH=3-4), and an excess of NaBH₃CN was added. The reaction wasmaintained for 2 d then concentrated. The crude reaction mixture wasdissolved in EtOAc and partitioned with aqueous saturated NaHCO3solution. The layers were separated and the aqueous phase was extractedwith EtOAc (3×). The combined organic portions were washed with brine,dried (MgSO₄), and concentrated. The resulting residue was purified byreverse-phase HPLC to afford N-methyl amine 2 as a TFA salt: ¹H NMR (300MHz, CD₃OD) δ 8.48 (d, J=5.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 2 H), 7.67 (d,J=9.4 Hz, 1 H), 7.43 (d, J=8.8 Hz, 2 h), 7.20 (dd, J=2.2, 9.4 Hz, 1 H),7.19 (d, J=2.2 Hz, 1H), 7.02 (d, J=2.2, 1 H), 6.90 (dd, J=2.2, 5.8 Hz, 1H), 4.27 (s, 2 H), 3.86 (s, 3 H), 2.76 (s, 3 H); LCMS m/z 438.5 (MH³⁰ ),t_(R)=1.85 min.

[0555] The following tabulated benzyl amines were prepared by the abovemethod as in Example 1036 using the appropriate amine. TABLE 14 LCMSTIME Example Structure (MH⁺) m/z t_(R) (min) 1037

549.1 1.62 1038

482.2 1.94 1039

494.1 1.59 1040

468.2 1.87 1041

483.3 1.83 1042

536.2 1.87 1043

552.2 1.84 1044

536.4 1.80 1045

522.3 1.76 1046

550.4 1.80 1047

452.3 2.70* 1048

521.4 3.63* 1049

465.3 2.75* 1050

467.3 2.86* 1051

494.2 1.82 1052

497.2 2.04

EXAMPLE 1053[5-(2-Aminomethyl-pyridin-4-yloxy)-1-methyl-1H-benzoimidazol-2-yl]-(4-bromophenyl)-amine

[0556]

[0557] LAH (98 mg, 2.5 mmol) was added portionwise to a stirringsolution of oxime 1 (225 mg, 0.5 mmol) in dry THF (3 mL) at 0° C. Afteraddition, the cooling bath was removed and the reaction was allowed towarm to rt overnight. The reaction was quenched by addition of water(0.1 mL), 10% w/w aqueous NaOH solution (0.1 mL), and 10 water (0.3 mL).The resulting slurry was stirred at rt for 1 h and filtered throughCelite. The remaining solids were rinsed with EtOAc and the organicportions were combined and concentrated. The crude residue was purifiedby reverse-phase HPLC to provide benzyl amine 2 as a TFA salt: LCMS m/z424.1 (MH³⁰ ), t_(R)=1.87 min.

EXAMPLE 1054{4-[2-(4-Bromophenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-yl-methyl]-carbamicacid methyl ester

[0558]

[0559] Methyl chloroformate (6 μL, 0.08 mmol) was added to a solution ofbenzyl amine 1 (21 mg, 0.05 mmol) and triethylamine (69 μL, 0.5 mmol) indry THF (1 mL) at 0° C. The reaction was maintained at 0° C. for 20 min,then at rt for 2 h. The reaction mixture was concentrated and purifiedby reverse-phase HPLC to provide methyl carbamate 2 as a TFA salt: LCMSm/z,482.2 (MH³⁰ ), t_(R)=1.96 min.

EXAMPLE 1055N-{4-[2-(4-Bromophenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-ylmethyl}acetamide

[0560]

[0561] To a solution of benzyl amine 1 (17 mg, 0.04 mmol) in dry NMP (2mL) was added triethylamine (0.06 mL, 0.4 mmol) and acetic anhydride(0.04 mL, 0.4 mmol). The resulting reaction was maintained at rtovernight and purified directly by reverse-phase HPLC to furnishacetamide 2 as a TFA salt: LCMS m/z 466.3 (MH³⁰ ), t_(R)=1.78 min.

EXAMPLE 10564-[2-(3-Ethylphenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pryidine-2-carboxylicacid [3-(2-oxo-pyrrolidin-yl)-propyl]-amide General Preparation forN-(3-Aminopropyl)-pyrolidinone Amides

[0562] Step 1: 4-Chloro-pyridine-2-carboxylic acid[3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide

[0563] Acid chloride 1 (2.12 g, 10 mmol) was treated withN-methylmorpholine (4.5 mL, 41 mmol) and N-(3-aminopropyl)-pyrrolidinone2 (1.6 mL, 11 mmol) in dry THF (40 mL). The reaction was maintainedovernight and concentrated. The residue was dissolved in EtOAc andpartitioned with water. The aqueous portion was extracted with EtOAc(3×) and the combined organic phases were washed with brine, dried(MgSO₄), and concentrated. The crude residue was purified by Kugelrohrdistillation (0.5 mmHg, 170-200° C.) to provide 3.

[0564] Step 2: 4-(4-Methylamino-3-nitrophenoxy)-pyridine-2-carboxylicacid [3-(2-oxo-pyrrolidin-yl)-propyl]-amide

[0565] Prepared as per Example 120b with the appropriate substitutions.Amide 3 can be purified by flash chromatography (95:5 CH₂Cl₂-MeOH). Itcan also be further purified by recrystallization from MeCN.

[0566] Step 3: 4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carboxlicacid [3-(2-oxo-pyrrolidin-yl)-propyl]-amide

[0567] Prepared as per Example 120b.

[0568] Step 4:4-[2-(3-Ethylphenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pryidine-2-carboxylicacid [3-(2-oxo-pyrrolidin-yl)-propyl]-amide.

[0569] Prepared as per Example 120b to provide benzimidazole 2 as a TFAsalt: LCMS m/z 513.3 (MH³⁰ ), t_(R)=2.22 min.

[0570] Prepared as per Example 1056: LCMS m/z 563.2 (MH³⁰ ), t_(R)=2.15min.

[0571] Prepared as per Example 1056: LCMS t_(R)=585.3 (MH³⁰ ),t_(R)=2.55 min.

[0572] Prepared as per Example 1056: LCMS m/z 563.2 (MH³⁰ ), t_(R)=2.50min.

[0573] The following additional compounds were prepared following theprocedures of the indicated Examples: TABLE 15 Synthesized ExampleStructure Name MH+ as in Ex.: 1060

N-methyl-4-[(2-{[3-(2-methyl- pyridin-4-yl)phenyl]amino }-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 451.5 702 1061

N-methyl-4-[(1-methyl-6- (methyloxy)-2-{[3-(2-methyl-pyridin-4-yl)phenyl]amino }-1H- benzimidazol-5-yl)oxy]pyridine-2-carboxamide 505.5 702 1062

N-methyl-4-{[2-({3-[3-(tri- fluoromethyl)pyridin-4-yl]-phenyl}amino)-1H-benz- imidazol-5-yl]oxy}pyridine-2- carboxamide 505.5702 1063

N-methyl-4-{[1-methyl-6- (methyloxy)-2-({3-[3-(trifluoro-methyl)pyridin-4-yl]phenyl}- amino)-1H-benzimidazol-5-yl]-oxy}pyridine-2-carboxamide 549.5 702 1064

4-[(2-{[3-(2-fluoropyridin-4- yl)phenyl]amino}-1H-benz-imidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 455.5 702 1065

4-{[2-{[3-(2-fluoropyridin-4- yl)phenyl]amino}-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-methylpyridine-2- carboxamide499.5 702 1066

4-[(2-{[3-(2-fluoropyridin-4-yl)- 4-methylphenyl]amino}-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 469.5 702 1067

4-{[2-({3-(2-fluoropyridin-4-yl)- 4-[(trifluoromethyl)oxy]-phenyl}amino)-1H-benz- imidazol-5-yl]oxy}-N-methyl-pyridine-2-carboxamide 1068

4-[(2-{[3-(2-fluoropyridin-4-yl)- methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-(2-hydroxyethyl)-pyridine-2-carboxamide 513.5 483 1069

4-[(2-{[3-(2-fluoropyridin-4-yl)- 4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-[3-(2-oxopyrrolidin-1-yl)propyl]pyridine-2-carbox- amide 594.7 483 1070

N-[2-(dimethylamino)ethyl]-4- [(2-{[3 -(2-fluoropyridin-4-yl)-4-methylphenyl]amino}-1-methyl- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 540.6 483 1071

4-[(2-{[3-(2-fluoropyridin-4-yl)- methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-(2-morpholin-4-ylethyl)-pyridine-2-carboxamide 582.6 483 1072

4-[(2-{[3-(2-fluoropyridin-4-yl)- methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-(2,2,2-trifluoroethyl)-pyridine-2-carboxamide 551.5 483 1073

4-[(2-{[3-(2-fluoropyridin-4-yl)- 4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-(2-piperazin-1-ylethyl)-pyridine-2-carboxamide 581.7 483 1074

N-[2-(acetylamino)ethyl]-4-[(2- {[3-(2-fluoropyridin-4-yl)-4-methyiphenyl]amino}-1-methyl- 1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 554.6 483 1075

4-[(2-{[3-(2-fluoropyridin-4-yl)- 4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-(2-piperidin-1 -ylethyl)-pyridine-2-carboxamide 580.7 483 1076

4-[(2-{[3-(2-fluoropyridin-4-yl)- 4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-[1-(1-methylethyl)-azetidin-3-yl]pyridine-2-carbox- amide 566.7 636 1077

4-[(2-{[3-(2-fluoropyridin-4-yl)- 4-(methyloxy)phenyl]methyl}-1-methyl-1H-benzimidazol-5-yl)- oxy]-N-methylpyridine-2- carboxamide 498.5636 1078

N-methyl-4-({1-methyl-2-[(4- methylphenyl)methyl]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 387.5 636 1079

N-methyl-4-[(1-methyl-2-{[4- (methyloxy)phenyl]methyl}-1H-benzimidazol-5-yl)oxy]pyridine- 2-carboxamide 403.5 636 1080

N-methyl-4-[(1-methyl-2-{[4-(1- methylethyl)phenyl]methyl}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 415.5 636 1081

N-methyl-4-{[1-methyl-2-({4-[(trifluoromethyl)oxy]phenyl}methyl)-1H-benzimidazol-5-yl]-oxy}pyridine-2-carboxamide 457.4 636 1082

4-({2-[(4-chlorophenyl)methyl]- 1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 407.9 636 1083

N-methyl-4-[(1-methyl-2-{[4- (trifluoromethyl)phenyl]methyl}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 441.4 636 1084

4-{[2-{[3-(1,1-dimethylethyl)- phenyl]amino}-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-methylpyridine-2- carboxamide460.5 703 1085

N-methyl-4-{[1methyl-2-{[3- (1-methylethyl)phenyl]amino}-6-(methyloxy)-1H-benz- imidazol-5-yl]oxy}pyridine-2- carboxamide 446.5703 1086

N-methyl-4-[(2-{[3-(1-methyl- ethyl)phenyl]amino}-1H-benz-imidazol-5-yl)oxy]pyridine-2- carboxamide 402.5 1 1087

4-[(2-{[4-(1,1-dimethylethyl)-3- (2-fluoropyridin-4-yl)phenyl]-amino}-1-methyl-1H-benz- imidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide 525.6 702 1088

4-{[2-{[4-(1,1-dimethylethyl)-3- (2-fluoropyridin-4-yl)phenyl]-amino}-1methyl-6-(methyl- oxy)-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2- carboxamide 555.6 702 1089

4-[(2-{[4-(1,1-dimethylethyl)-3- (2-fluoropyridin-4-yl)phenyl]-amino}-1H-benzimidazol-5-yl)- oxy]-N-methylpyridine-2- carboxamide 511.6702 1090

4-{[2-{[3 -(2-fluoropyridin-4-yl)- 4-methylphenyl]amino}-1-methyl-6-(methyloxy)-1H- benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide 513.5 702 1091

4-[(2-{[3-(2,6-dimethylpyridin- 4-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 479.6 702 1092

4-[(2-{[3-(2,6-dimethylpyridin- 4-yl)phenyl]amino}-1H-benz-imidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 465.5 702 1093

4-{[2-{[3-(2,6-dimethylpyridin- 4-yl)phenyl]amino}-1-methyl-6-(methyloxy)-1H-benzimidazol- 5-yl]oxy}-N-methylpyridine-2- carboxamide509.6 702  1094a

N-methyl-4-({1-methyl-2-[(4- methyl-3-thien-2-ylphenyl)-amino]-1H-benzimidazol-5-yl}- oxy)pyridine-2-carboxamide 470.6 702

N-methyl-4-({1-methyl-2-[(3- thien-3-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 456.5 702

General Preparation for Phenolic Benzimidazoles3-Amino-4-methylaminophenol

[0574]

[0575] Diamine 2 prepared as per Example 120b from nitroaniline 1.

EXAMPLE 1095 2-(3-Bromophenylamino)-1-methyl-1H-benzoimidazol-5-ol

[0576]

[0577] Benzimidazole 2 was prepared as per Example 120b: LCMS m/z 318.1(MH³⁰ ), t_(R)=2.07min.

[0578] LCMS m/z 332.1 (MH³⁰ ), t_(R)=2.22 min

[0579] LCMS m/z 366.1 (MH³⁰ ), t_(R)=2.13 min

[0580] LCMS m/z 340.2 (MH³⁰ ), t_(R)=2.39 min

EXAMPLE 1099 Preparation of Symmetrical bis-Benzimidazoles

[0581] Step 1: 4,4′-dimethylamino-3,3′-dinitro diphenyl ether

[0582] Diphenyl ether 2 was prepared using the method described inExample 120b: ¹H NMR (300 MHz, CDCl₃) δ 7.98 (br s, 2 H), 7.75 (d, J=3.0Hz, 2 H), 7.29 (app d, J=3.0 Hz, 1 H), 6.87 (d, J=9.5 Hz, 2 H), 3.05 (d,J=5.2 Hz, 6 H).

[0583] Step 2: 4,4′-dimethylamino-3,3′-diamino diphenyl ether

[0584] Tetramine 2 was prepared as per Example 120b: ¹H NMR (300 MHz,CDCl₃) δ 6.59 (d, J=8.5 Hz, 2 H), 6.47 (dd, J=2.8, 8.5 Hz, 2 H), 6.41(d, J=2.8 Hz, 2 H), 3.40 (br s, 4 H), 3.06 (br s, 2 H), 2.84 (d, J=5.5Hz, 6 H).

EXAMPLE 1100bis-5-[2-(3-Bromophenylamino)-1-methyl-1H-benzoimidazole]-ether

[0585]

[0586] Prepared as per Example 120b: LCMS m/z 617.1 (MH³⁰ ), t_(R)=2.27min

[0587] Prepared as per Example 120b: LCMS m/z 573.4 (MH³⁰ ), t_(R)=2.78min

[0588] Prepared as per Example 120b: LCMS m/z 661.2 (MH³⁰ ), t_(R)=2.83min

[0589] Prepared as per Example 120b: LCMS m/z 545.4 (MH³⁰ ), t_(R)=2.73min

[0590] Prepared as per Example 120b: LCMS m/z 461.3 (MH³⁰ ), t_(R)=1.98min

EXAMPLE 1105 Preparation of Benzo Derivatives2-(N-Phthalimido)-4-fluororntrobenzene

[0591]

[0592] A suspension of 2,4 difluoronitrobenzene (15.9 g, 100 mmol) andpotassium phthalimide (16.5 g, 100 mmol) was stirred in dry NMP (50 mL)for 3 d. The reaction solution was poured into MTBE and the resultingprecipitate was collected by filtration. The solids were washed withMTBE (3×) and the mother liquor was extracted with MTBE (3×). Thecombined organic portions were washed with water (3×) and concentratedto furnish a yellow solid which was combined with the initial crop ofprecipitate. The combined crude solid was purified by recrystallizationfrom hot toluene, and the crystals were washed with cold MTBE: ¹H NMR(300 MHz, d⁶-DMSO) δ 8.31 (dd, J=5.2, 9.1 Hz, 1 H), 7.98 (m, 4 H), 7.69(dd, J=2.8, 9.1 Hz, 1 H), 7.62 (ddd, J=1.7, 2.8, 7.7 Hz, 1 H).

EXAMPLE 1106 2-(N-Phthalimido)-4-phenoxynitrobenzene

[0593]

[0594] 2-(N-Phthalimido)-4-phenoxynitrobenzene 2 was prepared using asimilar procedure employed in Example 120b.

EXAMPLE 1107 2-(N-Phthalimido)-4-phenoxyaniline

[0595]

[0596] 2-(N-Phthalimido)-4-phenoxyaniline 2 was obtained through thereduction of 2-(N-phthalimido)-4-phenoxynitrobenzene 1. as described inExample 120b.

EXAMPLE 1108 N-[2-(N-Phthalimido)-4-phenoxy-phenyl]-formamide

[0597]

[0598] A mixture of formic acid (0.12 mL, 5.3 mmol) and acetic anhydride(0.24 mL, 2.5 mmol) was heated to 60° C. for 2 h. After allowing to coolto rt, a solution of aniline 1 (387 mg, 1.0 mmol) in dry THF (1 mL) wasadded and the reaction was maintained overnight. The reaction wasconcentrated and the resulting crude residue was directly used in thenext step.

EXAMPLE 1109 N-Methyl-[2-(N-phthalimido)-4-phenoxy]-aniline

[0599]

[0600] A solution of formamide 1 was treated with BH₃-DMS solution (2.0M in CH₂Cl₂, 0.5 mL, 1.0 mL) and the reaction was allowed to warm to rtovernight. The reaction was concentrated and the resulting residue wasdissolved in EtOAc. The solution was partitioned with saturated aqueousNaHCO₃ solution and the layers were separated. The aqueous phase wasextracted with EtOAc (3×) and the combined organics phases were washedwith brine, dried (MgSO₄), adsorbed onto SiO₂ and purified by flashchromatography (4:1 hexanes-EtOAc) to furnish 2 as a colorless residue.

EXAMPLE 1110 N1-Methyl-4-phenoxybenzene-1,2-diamine

[0601]

[0602] Hydrazine monohydrate (0.13 mL, 2.7 mmol) was added to a solutionof phthalimide 1 (134 mg, 0.39 mmol) in ethanol (4 mL). The reaction wasmaintained overnight at rt and then was filtered through Celite. Thefilter cake was rinse with EtOAc (3×) and the organic portions werecombined and concentrated to give diamine 2 which was carried forwardwithout further purification: LCMS m/z 215.1 (MH³⁰ ), t_(R)=1.77 min.

EXAMPLE 1111 Synthesis of(4-Bromophenyl)-(1-methyl-5-phenoxy-1H-benzoimidazol-2-yl)-amine

[0603]

[0604] Benzimidazole 2 was prepared as per Example 120b: ¹H NMR (300MHz, CD₃OD) δ 7.68 (app ddd, J=2.9, 4.9, 8.8 Hz, 2 H), 7.53 (app d,J=8.8 Hz, 1 H), 7.41 (app ddd, J=2.9, 4.9, 8.8 Hz, 2 H), 7.40 (app ddd,J=1.0, 2.0, 8.5 Hz, 2 h), 7.24 (app ddd, J=1.0, 2.0, 8.5 Hz, 1 H), 7.07(app dd, J=2.2, 8.8 Hz, 1 H), 7.00 (app d, J=2.2 Hz, 1 H), 7.00 (appddd, J=1.0, 2.0, 8.5 Hz, 2 H), 3.82 (s, 3 H); LCMS m/z 394.0 (MH³⁰ ),t_(R)=2.36min.

EXAMPLE 1112

[0605]

[0606] A solution of 1 in MeCN was treated with aqueous 1 N HCl andfreeze dried. The resulting residue was purified by reverse-phase HPLCto provide vinyl chloride 2 as a TFA salt: LCMS m/z 434.2 (MH³⁰ ),t_(R)=2.48 min.

EXAMPLE 11134-[2-(3-Furan-3-yl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyrindine-2-carboxylicacid methyl amide

[0607]

[0608] A solution of Pd(OAc)₂ (4.5 mg, 0.02 mmol) and triphenylphosphine(13.1 mg 0.05 mmol) in dry NMP (I mL) was stirred at rt for 20 min. Aryliodide 1 (100 mg, 0.2 mmol), 3-furyl boronic acid (45 mg, 0.4 mmol), andtriethylamine (0.11 mL, 0.8 mmol) were added and the resulting solutionwas degassed and purged with Ar. The reaction was heated to 100° C. for2 h; LCMS indicated no conversion. The reaction was allowed to cool tort under Ar and Pd(dppf)Cl₂CH2Cl₂ and duisopropylethylamine (0.14 mL)were added. The reaction was heated to 100° C. and maintained overnight.The reaction was allowed to cool to rt and LCMS indicated completeconversion. The reaction was partitioned between saturated aqueousNaHCO₃ solution and EtOAc and the resulting mixture filtered throughCelite. The remaining solids were washed with water and EtOAc. Thecombined rinsings were partitioned and separated. The aqueous phase wasextracted with EtOAc (3×) and the combined organic portions were washedwith saturated aqueous Na₂CO₃, brine, dried (MgSO₄), and concentrated.The crude residue was purified by reverse-phase HPLC to furnish 2 as aTFA salt: LCMS m/z 440.3 (MH³⁰ ), t_(R)=2.35 min.

[0609] Prepared as per Example 120b.

[0610] Prepared as per Example 120b.

EXAMPLE 1116 Preparation of4-({2-[(4-chloro-3-pyridin-4-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide

[0611]

[0612] A solution of 1 (1 eq) and 10% palladium on carbon (0.1 eq) inethyl acetate was stirred at room temperature and flushed with nitrogen.Hydrogen was flushed through the reaction for 2-3 hours or until thereaction was determined to be complete by HPLC. Nitrogen was flushedthrough the reaction for 15 minutes before the reaction was filteredthrough a celite pad. The celite pad was washed with excess ethylacetate and methylene chloride before the combined organic solution wasremoved by evaporation under reduced pressure to afford the product as asolid 2. MS: MH⁺=207

[0613] A solution of 2 (1 eq) and sodium carbonate (1.5 eq) in acetonewas stirred under an atmosphere of nitrogen in an ice bath. Thiophosgene(1.5 eq) was added drop wise over 30 minutes. The reaction was stirredfor another 30 minutes in the ice bath before being removed and allowedto warm to RT. The reaction was stirred at RT for 1.5 h and thenconcentrated under vacuum. Toluene was added to the crude product andremoved under vacuum to azetrope off any residual thiophosgene andafford the product 3. MS: MH⁺=249

[0614] A solution of 3 (1.0 eq) and 4 (1.0 eq) in MeOH was stirred at RTovernight. Ferric chloride (1.2 eq) was added and the resulting reactionmixture was stirred overnight at RT. The reaction mixture wasconcentrated under vacuum. The crude product was partitioned with EtOAcand water and filtered. The layers were separated and the aqueous phasewas neutralized (pH=7) with saturated Na₂CO₃ solution. The resultingaqueous phase was extracted with EtOAc. The combined organic layers werewashed with brine, dried (Na₂SO₄), and concentrated to give the desiredproduct 5. MS: MH⁺=487

[0615] A solution of 5 (1 eq), 6 (1 eq), and sodium carbonate (1.2 eq)in DME/H₂O (3:1) was degassed by bubbling argon through the solution for10 minutes. Pd(II)(dppf)Cl₂. MeCl₂ (0.1 eq) was added to the reactionsolution and the reaction was sealed. The reaction was heated at 100° C.overnight. The reaction was cooled to RT and ethyl acetate and waterwere added. The organic layer was separated from the aqueous layer. Theaqueous layer was washed once more with ethyl acetate. The organiclayers were combined, dried (Na₂SO₄), and concentrated under vacuum toyield the desired product4-({2-[(4-chloro-3-pyridin-4-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide.MS: MH⁺=469

EXAMPLE 1117 Preparation of4-({2-[(4-fluoro-3-pyridin-4-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide

[0616]

[0617] A solution of 1 (1 eq) and 10% palladium on carbon (0.1 eq) inethyl acetate was stirred at room temperature and flushed with nitrogen.Hydrogen was flushed through the reaction for 2-3 hours or until thereaction was determined to be complete by HPLC. Nitrogen was flushedthrough the reaction for 15 minutes before the reaction was filteredthrough a celite pad. The celite pad was washed with excess ethylacetate and methylene chloride before the combined organic solution wasremoved by evaporation under reduced pressure to afford the product as asolid 2. MS: MH⁺=190

[0618] A solution of 2 (1 eq) and sodium carbonate (1.5 eq) in acetonewas stirred under an atmosphere of nitrogen in an ice bath. Thiophosgene(1.5 eq) was added drop wise over 30 minutes. The reaction was stirredfor another 30 minutes in the ice bath before being removed and allowedto warm to RT. The reaction was stirred at RT for 1.5 h and then thereaction solution was concentrated under vacuum. Toluene was added tothe crude product and removed under vacuum to azetrope off any residualthiophosgene and afford the product 3. MS: MH⁺=232

[0619] A solution of 3 (1.0 eq) and 4 (1.0 eq) in MeOH was stirred at RTovernight. Ferric chloride (1.2 eq) was added and the resulting reactionmixture was stirred overnight at RT. The reaction mixture wasconcentrated under vacuum. The crude product was partitioned with EtOAcand water and filtered. The layers were separated and the aqueous phasewas neutralized (pH=7) with saturated Na₂CO₃ solution. The resultingaqueous phase was extracted with EtOAc. The combined organic layers werewashed with brine, dried (Na₂SO₄), and concentrated to give the desiredproduct 5. MS: MH⁺=470

[0620] A solution of 5 (1 eq), 6 (1 eq), and sodium carbonate (1.2 eq)in DME/H₂O (3:1) was degassed by bubbling argon through the solution for10 minutes. Pd(II)(dppf)Cl₂. MeCl₂ (0.1 eq) was added to the reactionsolution and the reaction was sealed. The reaction was heated at 100° C.overnight. The reaction was cooled to RT and ethyl acetate and waterwere added. The organic layer was separated from the aqueous layer. Theaqueous layer was washed once more with ethyl acetate. The organiclayers were combined, dried (Na₂SO₄), and concentrated under vacuum toyield the desired product4-({2-[(4-fluoro-3-pyridin-4-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide. MS: MH⁺=453

EXAMPLE 1118 Preparation of4-({2-[(2-methoxy-5-pyridin-4-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide

[0621]

[0622] A solution of 1 (1 eq), acetonitrile, and glacial acetic acid (15eq) was stirred in an ice bath. Iron powder (7 eq) was added slowlyportion-wise. The reaction was left to stir overnight. The reactionsolution was filtered, diluted with ethyl acetate, and neutralized with3N sodium hydroxide. The organic phase was separated and the aqueousphase was washed once more with ethyl acetate. The organic layers werecombined, washed with water and brine, dried over sodium sulfate, andthe solvent was removed by evaporation under reduced pressure to affordthe product as a solid 2. MS: MH⁺=202

[0623] A solution of 2 (1 eq) and sodium carbonate (1.5 eq) in acetonewas stirred under an atmosphere of nitrogen in an ice bath. Thiophosgene(1.5 eq) was added drop wise over 30 minutes. The reaction was stirredfor another 30 minutes in the ice bath before being removed and allowedto warm to RT. The reaction was stirred at RT for 1.5 h and then thereaction solution was concentrated under vacuum. Toluene was added tothe crude product and removed under vacuum to azetrope off any residualthiophosgene and afford the product 3. MS: MH⁺=244

[0624] A solution of 3 (1.0 eq) and 4 (1.0 eq) in MeOH was stirred at RTovernight. Ferric chloride (1.2 eq) was added and the resulting reactionmixture was stirred overnight at RT. The reaction mixture wasconcentrated under vacuum. The crude product was partitioned with EtOAcand water and filtered. The layers were separated and the aqueous phasewas neutralized (pH=7) with saturated Na₂CO₃ solution. The resultingaqueous phase was extracted with EtOAc. The combined organic layers werewashed with brine, dried (Na₂SO₄), and concentrated to give the desiredproduct 5. MS: MH⁺=482

[0625] A solution of 5 (1 eq), 6 (1 eq), and sodium carbonate (1.2 eq)in DME/H₂O (3:1) was degassed by bubbling argon through the solution for10 minutes. Pd(II)(dppf)Cl₂. MeCl₂ (0.1 eq) was added to the reactionsolution and the reaction was sealed. The reaction was heated at 100° C.overnight. The reaction was cooled to RT and ethyl acetate and waterwere added. The organic layer was separated from the aqueous layer. Theaqueous layer was washed once more with ethyl acetate. The organiclayers were combined, dried (Na₂SO₄), and concentrated under vacuum toyield the desired product4-({2-[(2-methoxy-5-pyridin-4-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide.MS: MH⁺=465

EXAMPLE 1119 Preparation of4-({2-[(3-fluoro-2-methoxy-5-pyridin-4-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide

[0626]

[0627] A solution of 1 (1 eq), acetonitrile, and glacial acetic acid (15eq) was stirred in an ice bath. Iron powder (7 eq) was added slowlyportion-wise. The reaction was left to stir overnight. The reactionsolution was filtered, diluted with ethyl acetate, and neutralized with3N sodium hydroxide. The organic phase was separated and the aqueousphase was washed once more with ethyl acetate. The organic layers werecombined, washed with water and brine, dried over sodium sulfate, andthe solvent was removed by evaporation under reduced pressure to affordthe product as a solid 2. MS: MH⁺=220

[0628] A solution of 2 (1 eq) and sodium carbonate (1.5 eq) in acetonewas stirred in an ice bath under an atmosphere of nitrogen. Thiophosgene(1.5 eq) was added drop wise over 30 minutes. The reaction was stirredfor another 30 minutes in the ice bath before being removed and allowedto warm to RT. The reaction was stirred at RT for 1.5 h before thereaction solution was concentrated under vacuum. Toluene was added tothe crude product and removed under vacuum to azetrope off any residualthiophosgene and afford the product 3. MS: MH⁺=262

[0629] A solution of 3 (1.0 eq) and 4 (1.0 eq) in MeOH was stirred at RTovernight. Ferric chloride (1.2 eq) was added and the resulting reactionmixture was stirred overnight at RT. The reaction mixture wasconcentrated under vacuum. The crude product was partitioned with EtOAcand water and filtered. The layers were separated and the aqueous phasewas neutralized (pH=7) with saturated Na₂CO₃ solution. The resultingaqueous phase was extracted with EtOAc. The combined organic layers werewashed with brine, dried (Na₂SO₄), and concentrated to give the desiredproduct 5. MS: MH⁺=500

[0630] A solution of 5 (1 eq), 6 (1 eq), and sodium carbonate (1.2 eq)in DME/H₂O (3:1) was degassed by bubbling argon through the solution for10 minutes. Pd(II)(dppf)Cl₂. MeCl₂ (0.1 eq) was added to the reactionsolution and the reaction was sealed. The reaction was heated at 100° C.overnight. The reaction was cooled to RT and ethyl acetate and waterwere added. The organic layer was separated from the aqueous layer. Theaqueous layer was washed once more with ethyl acetate. The organiclayers were combined, dried (Na₂SO₄), and concentrated under vacuum toyield the desired product4-({2-[(3-fluoro-2-methoxy-5-pyridin-4-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide.MS: MH⁺=483

EXAMPLE 1120 Preparation ofN-methyl-4-({1-methyl-2-[(4-pyridin-4-yl-1,3-thiazol-2-yl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide

[0631]

[0632] A solution of 1 (1 eq) and sodium carbonate (1.5 eq) in acetonewas stirred in an ice bath under an atmosphere of nitrogen. Thiophosgene(1.5 eq) was added drop wise over 30 minutes. The reaction was stirredfor another 30 minutes in the ice bath before being removed and allowedto warm to RT. The reaction was stirred at RT for 1.5 h before thereaction solution was concentrated under vacuum. Toluene was added tothe crude product and removed under vacuum to azetrope off any residualthiophosgene and afford the product 2. MS: MH⁺=219

[0633] A solution of 2 (1.0 eq) and 3 (1.0 eq) in MeOH was stirred at RTovernight. Ferric chloride (1.2 eq) was added and the resulting reactionmixture was stirred overnight at RT. The reaction mixture wasconcentrated under vacuum. The crude product was partitioned with EtOAcand water and filtered. The layers were separated and the aqueous phasewas neutralized (pH=7) with saturated Na₂CO₃ solution. The resultingaqueous phase was extracted with EtOAc. The combined organic layers werewashed with brine, dried (Na2SO₄), and concentrated to give the desiredproductN-methyl-4-({1-methyl-2-[(4-pyridin-4-yl-1,3-thiazol-2-yl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide.MS: MH⁺=457

EXAMPLE 1121 Preparation of4-({2-[(3-ethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeO-methyloxime

[0634]

[0635] A 25 mL round bottom flask was charged with a suspension of 1(600 mg, 2.2 mmol), methoxyamine HCl (202 mg, 2.42 mmol), and pyridine(0.22 mL, 2.6 mmol) in ethanol (9 mL) and stirred at RT overnight. Crudeproduct concentrated and absorbed onto silica gel, then chromatographedusing 97:3 CH₂Cl₂/MeOH to give 2 as an orange solid. LCMS m/z 303.2(MH³⁰ ), R_(t) 2.40 min.

[0636] A sealed tube was charged with suspension of 1 (270 mg, 0.9 mmol)and Lindlar catalyst (192 mg, 10 mol %) in methanol (5 mL) then placedon a Parr shaker. Reaction purged with H₂ at 60 psi for 1 h. Solidsfiltered through Celite and washed with methanol, then concentrated togive 2 as a brown semi-solid. LCMS m/z 273.3 (MH³⁰ ), R_(t) 1.56 min.

[0637] Alternate Procedure:

[0638] A suspension of nitroaniline 1 (2.62 g, 8.67 mmol) in methanol(35 mL) was sparged with N₂ for 20 min after which 10% Pd/C (4.6 g, 43.4mmol) was added. The reaction was purged with H₂ and maintained under aH₂ atmosphere for 1 hr at rt. The reaction was purged with N₂ andfiltered through Celite. The collected solids were washed with EtOAc(3×100 mL), and the combined organic layers were concentrated to afford2 as an off-white semi solid. LCMS m/z 282.3 (MH³⁰ ), R_(t) 0.46 min.

[0639] A 5 mL round bottom flask was charged with3-ethylphenylisothiocyanate (24 mg, 0.1 mmol), diamine 1 (27 mg, 0.1mmol), and MeOH (0.5 mL) and the reaction was maintained at rtovernight. Methyl iodide (8 μL, 0.13 mmol) was added and the reactionstirred overnight at rt. The reaction was concentrated and the resultingresidue was purified by reverse-phase HPLC to obtain the desiredproduct. LCMS m/z 402.3 (MH³⁰ ), R_(t) 2.09min.

EXAMPLE 1122 Preparation of4-({2-[(3-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeO-methyloxime

[0640]

[0641] Synthesized as described above in Step 3 of Example 1121 using3-isopropylphenylisiothiocyanate. LCMS m/z 416.3 (MH³⁰ ), R_(t) 2.22min.

EXAMPLE 1123 Preparation of4-({2-[(3-tert-butylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeO-methyloxime

[0642]

[0643] Synthesized as described above in Step 3. of Example 1121 using3-tert-butylphenylisiothiocyanate. LCMS m/z 430.3 (MH³⁰ ), R_(t) 2.42min.

EXAMPLE 1124 Preparation of4-({2-[(3-isopropoxyphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeO-methyloxime

[0644]

[0645] Synthesized as described above in Step 3 of Example 1121 using3-isopropoxy-phenylisiothiocyanate. LCMS m/z 432.3 (MH³⁰ ), R_(t) 2.13min.

EXAMPLE 1125 Preparation of4-({1-methyl-2-[(3-phenoxyphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeO-methyloxime

[0646]

[0647] Synthesized as described above in Step 3 of Example 1121 using3-phenoxy-phenylisiothiocyanate. LCMS m/z 466.3 (MH³⁰ ), R_(t) 2.33 min.

EXAMPLE 1126 Preparation of4-({2-[(4-chlorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeoxime

[0648]

[0649] A flame dried 500 mL three necked round bottom flask purged withN₂ was charged with LAH (3.0 g, 75.0 mmol) and dry THF (240 mL). Theresulting suspension was cooled to 0° C. and t-butyl ester 1 (20.7 g, 60mmol) was slowly added while keeping the internal reaction temperatureunder 5° C. Reaction stirred at 0° C. for 2 hr followed by stirring atRT for overnight. NaBH₄ (2.27 g, 60 mmol) was added and stirred for anadditional hour at rt. After the reaction was judged complete, thestirred reduction mixture was treated with successive dropwise additionof 3 mL H₂O, 3 mL NaOH, and 9 mL H₂O. Reaction mixture filtered throughCelite, washed with ethyl acetate and methanol, and evaporated. Crudeproduct absorbed onto silica gel and chromatographed using 97:3CH₂Cl₂/MeOH to give 2 as an orange solid. ¹H NMR (300 MHz, CDCl₃) δ 8.40(d, J=5.5 Hz, 1 H), 8.05 (br s, 1H), 7.96 (d, J=2.75 Hz, 1 H), 7.29 (d,J=2.75 Hz, 1 H), 6.92 (d, J=9.35 Hz, 1 H), 6.75 (m, 2 H), 4.68 (s, 2 H),3.07 (d, J=5.23 Hz, 3 H).

[0650] Alternate Procedure:

[0651] A flame dried 2 L three necked round bottom flask purged with N₂was charged with LAH (2.32 g, 58.0 mmol) and dry THF (60 mL). Theresulting suspension was cooled to 0° C. and a suspension of t-butylester 1 (10.0 g, 29.0 mmol) in dry THF (60 mL) was slowly added whilekeeping the internal reaction temperature under 5° C. Reaction stirredat 0° C. for 30 min followed by stirring at RT for 30 min. After thereaction was judged complete, the stirred reduction mixture was treatedwith successive dropwise addition of 2.3 mL H₂O, 2.3 mL NaOH, and 7.2 mLH₂O. Reaction mixture filtered through Celite, washed with ethyl acetateand methanol, and evaporated. Crude product absorbed onto silica gel andchromatographed using 97:3 CH₂Cl₂/MeOH to give 2 as an orange solid. ¹HNMR (300 MHz, CDCl₃) δ 8.40 (d, J=5.5 Hz, 1 H), 8.05 (br s, 1H), 7.96(d, J=2.75 Hz, 1 H), 7.29 (d, J=2.75 Hz, 1 H), 6.92 (d, J 9.35 Hz, 1 H),6.75 (m, 2 H), 4.68 (s, 2 H), 3.07 (d, J=5.23 Hz, 3 H).

[0652] A 250 mL sealed tube was charged with benzyl alcohol 1 (1.0 g,3.6 mmol), MnO₂ (4.7 g, 54 mmol) and EtOAc (20 mL). The resultingsuspension was heated to 120° C. with stirring for 2 hours. Reactionmixture filtered through Celite and washed successively with EtOAc,MeOH, and EtOH. Organics evaporated to give 936 mg (3.4 mmol, 94%) of 2as an orange solid. ¹H NMR (300 MHz, CDCl₃) δ 10.01 (s, 1 H), 8.64 (d,J=5.5 Hz, 1 H), 8.09 (br s, 1 H), 7.96 (d, J=2.75 Hz, 1 H), 7.37 (d,J=2.48 Hz, 1 H), 7.29 (d, J=2.75 Hz, 1 H), 7.08 (dd, J=2.47, 5.5 Hz, 1H), 6.94 (d, J=9.35 Hz, 1 H), 3.08 (d, J=5.23 Hz, 3 H).

[0653] Alternate procedure:

[0654] A 100 mL round bottom flask was charged with benzyl alcohol 1(1.38 g, 5.0 mmol), MnO₂ (6.52 g, 75 mmol) and CHCl₃ (20 mL). Theresulting suspension stirred at rt overnight. Reaction mixture filteredthrough Celite, washed successively with CHCl₃ and EtOH, and evaporated.Crude product absorbed onto silica gel and chromatographed using 98:2CH₂Cl₂/MeOH to give 2 as an orange solid. ¹H NMR (300 MHz, CDCl₃) δ10.01 (s, 1 H), 8.64 (d, J=5.5 Hz, 1 H), 8.09 (br s, 1 H), 7.96 (d,J=2.75 Hz, 1 H), 7.37 (d, J=2.48 Hz, 1 H), 7.29 (d, J=2.75 Hz, 1 H),7.08 (dd, J=2.47, 5.5 Hz, 1 H), 6.94 (d, J=9.35 Hz, 1 H), 3.08 (d,J=5.23 Hz, 3 H).

[0655] A 50 mL round bottom flask was charged with a suspension of 1(680 mg, 2.5 mmol), hydroxylamine HCl (191 mg, 2.75 mmol), and pyridine(0.25 mL, 3.0 mmol) in ethanol (10 mL) and stirred at RT overnight.Crude product concentrated and absorbed onto silica gel, thenchromatographed using 97:3 CH₂Cl₂/MeOH to give 2 as an orange solid.LCMS m/z 289.2 (MH³⁰ ), R_(t) 2.06 min.

[0656] A sealed tube was charged with suspension of 1 (330 mg, 1.15mmol) and Lindlar catalyst (245 mg, 10 mol %) in methanol (5 mL) thenplaced on a Parr shaker. Reaction purged with H₂ at 60 psi for 1 h.Solids filtered through Celite and washed with methanol, thenconcentrated to give 2 as a brown semi-solid. Taken on without furtherpurification.

[0657] A 5 mL round bottom flask was charged with4-chlorophenylisothiocyanate (54 mg, 0.25 mmol), diamine 1 (65 mg, 0.25mmol), and MeOH (1 mL) and the reaction was maintained at RT overnight.Methyl iodide (20 μL, 0.33 mmol) was added and the reaction stirredovernight at rt. The reaction was concentrated and the resulting residuewas purified by reverse-phase HPLC to yield the desired product. LCMSm/z 394.2 (MH³⁰ ), R_(t) 2.57 min.

EXAMPLE 1127 Preparation of4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeoxime

[0658]

[0659] Synthesized as described above in Step 3 of Example 1126 using4-methylphenylisiothiocyanate. LCMS m/z 374.3 (MH³⁰ ), R_(t) 2.48 min.

EXAMPLE 1128 Preparation of4-({2-[(4-bromo-2-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeoxime

[0660]

[0661] Synthesized as described above in Step 3 of Example 1126 using4-bromo-2-fluorophenylisiothiocyanate. LCMS m/z 458.1 (MH³⁰ ), R_(t)2.71 min.

EXAMPLE 1129 Preparation of4-[(1-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carbaldehydeoxime

[0662]

[0663] Synthesized as described above in Step 3 of Example 1126 using4-trifluoromethylphenylisiothiocyanate. LCMS m/z 428.2 (MH³⁰ ), R_(t)3.03 min.

EXAMPLE 1130 Preparation of4-({2-[(4-bromo-3-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeoxime

[0664]

[0665] Synthesized as described above in Step 3 of Example 1126 using4-bromo-3-fluorophenylisiothiocyanate. LCMS m/z 456.1 (MH³⁰ ), R_(t)2.92 min.

EXAMPLE 1131 Preparation of4-({2-[(2,4-dimethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeoxime

[0666]

[0667] Synthesized as described above in Step 3 of Example 1126 using2,4-dimethyl-phenylisiothiocyanate. LCMS m/z 388.3 (MH³⁰ ), R_(t) 2.62min.

EXAMPLE 1132 Preparation of 4-({2-[(34-dimethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeoxime

[0668]

[0669] Synthesized as described above in Step 3 of Example 1126 using3,4-dimethyl-phenylisiothiocyanate. LCMS m/z 388.3 (MH³⁰ ), R_(t) 2.71min.

EXAMPLE 1133 Preparation of4-{[2-(2,3-dihydro-1H-inden-5-ylamino)-1-methyl-1H-benzimidazol-5-yl]oxy}pyridine-2-carbaldehydeoxime

[0670]

[0671] Synthesized as described above in Step 3 of Example 1126 using5-indanyl-phenylisiothiocyanate. LCMS m/z 400.3 (MH³⁰ ), R_(t) 2.88 min.

EXAMPLE 1134 Preparation of4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridine-2-carbaldehydeoxime

[0672]

[0673] Synthesized as described above in Step 3 of Example 1126 using4-chloro-3-trifluoromethylphenylisiothiocyanate. LCMS m/z 462.2 (MH³⁰ ),R_(t) 3.45 min.

EXAMPLE 1135 Preparation of4-{[1-methyl-2-({3-[(trifluoromethyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2-carbaldehydeoxime

[0674]

[0675] Synthesized as described above in Step 3 of Example 1126 using3-trifluoromethylthiophenylisiothiocyanate. LCMS m/z 460.2 (MH³⁰ ),R_(t) 3.30 min.

EXAMPLE 1136 Preparation of4-({2-[(4-bromo-3-chlorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeoxime

[0676]

[0677] Synthesized as described above in Step 3 of Example 1126 using4-bromo-3-chlorophenylisiothiocyanate. LCMS m/z 472.1 (MH³⁰ ), R_(t)_(t) 3.17 min.

EXAMPLE 1137 Preparation of4-[(2-{[2-chloro-4-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridine-2-carbaldehydeoxime

[0678]

[0679] Synthesized as described above in Step 3 of Example 1126 using2-chloro-4-trifluoromethylphenylisiothiocyanate. LCMS m/z 462.2 (MH³⁰ ),R_(t) 3.39 min.

EXAMPLE 1138 Preparation of4-[(1-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy}pyridine-2-carbaldehydeoxime

[0680]

[0681] Synthesized as described above in Step 3 of Example 1126 using4-trifluoromethoxyphenylisiothiocyanate. LCMS m/z 444.2 (MH³⁰ ), R_(t)3.03 min.

EXAMPLE 1139 Preparation of4-[(2-{[4-bromo-2-(trifluoromethoxv)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridine-2-carbaldehydeoxime

[0682]

[0683] Synthesized as described above in Step 3 of Example 1126 using4-bromo-2-trifluoromethoxyphenylisiothiocyanate. LCMS m/z 524.1 (MH³⁰ ),R_(t) 3.28 min.

EXAMPLE 1140 Preparation of4-({2-[(3-ethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeoxime

[0684]

[0685] Synthesized as described above in Step 3 of Example 1126 using3-ethylphenylisiothiocyanate. LCMS m/z 388.3 (MH³⁰ ), R_(t) 2.75 min.

EXAMPLE 1141 Preparation of4-({2-[(3-methoxyphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeoxime

[0686]

[0687] Synthesized as described above in Step 3 of Example 1126 using3-methoxyphenylisiothiocyanate. LCMS m/z 390.3 (MH³⁰ ), R_(t) 2.35 min.

EXAMPLE 1142 Preparation of4-[(1-methyl-2-{[3-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carbaldehydeoxime

[0688]

[0689] Synthesized as described above in Step 3 of Example 1126 using3-trifluoromethylphenylisiothiocyanate. LCMS m/z 428.2 (MH³⁰ ), R_(t)2.92 min.

EXAMPLE 1143 Preparation of4-({2-[(4-ethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeoxime

[0690]

[0691] Synthesized as described above in Step 3 of Example 1126 using4-ethylphenylisiothiocyanate. LCMS m/z 388.3 (MH³⁰ ), R_(t) 2.79 min.

EXAMPLE 1144 Preparation of4-{[1-methyl-2-({4-[(trifluoromethyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2-carbaldehydeoxime

[0692]

[0693] Synthesized as described above in Step 3 of Example 1126 using4-trifluoromethylthiophenylisiothiocyanate. LCMS m/z 460.2 (MH³⁰ ),R_(t) 2.18 min.

EXAMPLE 1145 Preparation of4-({2-[(3-tert-butylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeoxime

[0694]

[0695] Synthesized as described above in Step 3 of Example 1126 using3-tert-butyl-phenylisiothiocyanate. LCMS m/z 416.4 (MH³⁰ ), R_(t) 2.31min.

EXAMPLE 1146 Preparation of4-({2-[(4-bromo-3-methylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeoxime

[0696]

[0697] Synthesized as described above in Step 3 of Example 1126 using4-bromo-3-methylphenylisiothiocyanate. LCMS m/z 454.2 (MH³⁰ ), R_(t)2.18 min.

EXAMPLE 1147 Preparation of4-({2-[(3,4-dichlorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeoxime

[0698]

[0699] Synthesized as described above in Step 3 of Example 1126 using3,4-dichloro-phenylisiothiocyanate. LCMS m/z 428.2 (MH³⁰ ), R_(t) 2.18min.

EXAMPLE 1148 Preparation of4-({2-[(3-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeoxime

[0700]

[0701] Synthesized as described above in Step 3 of Example 1126 using3-isopropyl-phenylisiothiocyanate. LCMS m/z 402.3 (MH³⁰ ), R_(t) 2.18min.

EXAMPLE 1149 Preparation of4-({2-[(3-isopropoxyphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeoxime

[0702]

[0703] Synthesized as described above in Step 3 of Example 1126 using3-isopropoxy-phenylisiothiocyanate. LCMS m/z 418.3 (MH³⁰ ), R_(t) 1.96min.

EXAMPLE 1150 Preparation of4-({1-methyl-2-[(3-phenoxyphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carbaldehydeoxime

[0704]

[0705] Synthesized as described above in Step 3 of Example 1126 using3-phenoxy-phenylisiothiocyanate. LCMS m/z 452.3 (MH³⁰ ), R_(t) 2.15 min.

EXAMPLE 1151 Preparation ofN-(3-tert-butylphenyl)-5-{[2-(1H-imidazol-2-yl)pyridin-4-yl]oxy}-1-methyl-1H-benzimidazol-2-amine

[0706]

[0707] A 10 mL round bottom flask was charged with suspension of 1 (273mg, 1.0 mmol), 40% glyoxal (0.4 mL), and 28% concentrated NH₄OH (0.6 mL)in MeOH (2 mL). Reaction was maintained at rt overnight. MeOH removedunder reduced pressure, H₂O was added to the residue and the solutionwas extracted 4× with CHCl₃. The combined extracts were washed withbrine, dried, and filtered. Crude product was concentrated, thenabsorbed onto silica gel and chromatographed. The product was elutedwith 99:1 CH₂Cl₂/MeOH to give 2 as an orange solid. LCMS m/z 312.3 (MH³⁰), R_(t) 2.09 min.

[0708] A suspension of nitroaniline 3 (116 mg, 0.37 mmol) in methanol (2mL) was sparged with N₂ for 20 min after which 10% Pd/C (40 mg, 0.37mmol) was added. The reaction was purged with H₂ and maintained under aH₂ atmosphere overnight at rt. The reaction was purged with N₂ andfiltered through Celite. The collected solids were washed with EtOAc(3×50 mL), and the combined organic layers were concentrated to afford 4as an off-white semi solid. LCMS m/z 282.3 (MH³⁰ ), R_(t) 0.46 min.

[0709] A 10 mL round bottom flask was charged with3-tert-butylphenylisothiocyanate (29 mg, 0.15 mmol), diamine 5 (42 mg,0.15 mmol), and MeOH (1 mL) and the reaction maintained at rt overnight.Ferric chloride (27 mg, 0.17 mmol) was added and the resulting redreaction mixture was stirred overnight. The reaction was neutralizedwith 15% w/w NaOH, partitioned with EtOAc (20 mL) and water (20 mL), andfiltered through Celite. The layers were separated and the resultingaqueous phase was extracted with EtOAc (3×20 mL). The combined organiclayers were washed with brine (50 mL), dried (MgSO₄), and concentrated.The resulting residue was purified by reverse-phase HPLC to give thedesired product. LCMS m/z 439.4 (MH³⁰ ), R_(t) 2.24 min.

EXAMPLE 1152 Preparation of5-{[2-(1H-imidazol-2-yl)pyridin-4-yl]oxy}-N-(3-isopropylphenyl)-1-methyl-1H-benzimidazol-2-amine

[0710]

[0711] Synthesized as described above in Step 3 of Example 1151 using3-isopropyl-phenylisiothiocyanate. LCMS m/z 425.4 (MH³⁰ ), R_(t) 2.15min.

EXAMPLE 1153 Preparation of5-{[2-(1H-imidazol-2-yl)pyridin-4-yl]oxy}-1-methyl-N-{4-[(trifluoromethyl)thio]phenyl}-1H-benzimidazol-2-amine

[0712]

[0713] Synthesized as described above in Step 3 of Example 1151 using4-trifluoromethylthiophenylisiothiocyanate. LCMS m/z 483.3 (MH³⁰ ),R_(t) 2.29 min.

EXAMPLE 1154 Preparation ofN-methyl-4-({1-methyl-2-[4-methyl-3-pyrrolidin-1-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide

[0714]

[0715] Step 1: Synthesis of (2-methyl-5-nitrophenyl)pyrrolidine

[0716] To the mixture containing 2-methyl-5-nitrophenylamine andpotassium carbonate (4 eq) in dimethyl formamide was added 1,2dibromobutane (4 eq) and the resulting mixture was stirred at 70° C. for16 hours. The reaction mixture was then concentrated and partitionedbetween ethyl acetate and water. The organic layer was dried with sodiumsulfate and concentrated and purified on silica gel to give(2-methyl-5-nitrophenyl)pyrrolidine.

[0717] MS: MH+=206.

[0718] Step 2: Synthesis of (4-methyl-3-pyrrolidinylphenyl amine

[0719] The mixture containing (2-methyl-5-nitrophenyl)pyrrolidine inmethanol with catalytic amount of 10% Pd/C was hydrogenated to yield4-methyl-3-pyrrolidinylphenylamine.

[0720] MS: MH+=176.

[0721] Step 3: Synthesis of3-(3-chlro(4-pyridyl))-4-methylbenzeneisothiocyanate

[0722] To (4-methyl-3-pyrrolidinylphenylamine in acetone at 0° C. wasadded sodium bicarbonate (2 eq) and thiophosgene (2 eq). The mixture wasbrought to ambient temperature and concentrated and partitioned betweenethyl acetate and water. The organic layer was dried with sodiumbicarbonate and sodium sulfate and concentrated to yield4-methyl-3-pyrrolidinylbenzeneisothiocyanate.

[0723] MS: MH+=218.

[0724] Step 4: Synthesis ofN-methyl-4-({1-methyl-2-[(4-methyl-3-pyrrolidin-1-ylphenyl)-amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide

[0725] To 4-methyl-3-pyrrolidinylbenzeneisothiocyanate (1 eq) inmethanol was added{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1eq) and the resulting mixture was stirred at ambient temperature for 16h. LC/MS shows formation of the corresponding thiourea. To it inmethanol was then added anhydrous ferric chloride (1.5 eq) and stirredfor 3 h. The reaction mixture was then concentrated to half its volumeand brought to neutral pH with 1N sodium hydroxide. It was thenextracted with ethyl acetate and the organic layer was washed with brineand dried with sodium sulfate. The crude was then triturated with hotmethanol to yield the desired product.

[0726] MS: MH+=456.

EXAMPLE 1154 Preparation of4-[(2-{[4-chloro-3-(2-oxopyrrolidin-1-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide

[0727]

[0728] 1. Synthesis of 4-chloro-3-nitrobenzeneisothiocyanate

[0729] To 4-chloro-3-nitrophenylamine in acetone at 0° C. was addedsodium bicarbonate (2 eq) and thiophosgene (2 eq). The mixture wasbrought to ambient temperature and concentrated and partitioned betweenethyl acetate and water. The organic layer was dried with sodiumbicarbonate and sodium sulfate and concentrated to yield4-chloro-3-nitrobenzeneisothiocyanate

[0730] MS: MH+=213.9.

[0731] 2. Synthesis of(4-{2-[(4-chloro-3-nitrophenyl)amino]-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide

[0732] To 4-chloro-3-nitrobenzeneisothiocyanate (1 eq) in methanol wasadded{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1eq) and stirred at ambient temperature for 16 h. The correspondingthiourea formation was followed by LC/MS. To it was the addediodomethane (1 eq) and heated to 60° C. for 3 h. Concentration followedby purification on silica gel(4-{2-[(4-chloro-3-nitrophenyl)-amino]-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide

[0733] MS: MH+=452.1.

[0734] 3. Synthesis of(4-{2-[(3-amino-4-chlorophenyl)amino]-1-methyl)amino]-1-methyl-benzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide.

[0735] To(4-{2-[(4-chloro-3-nitrophenyl)amino]-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamidein acetic acid was added Fe dust (3 eq) and stirred at ambienttemperature for 16 h. The mixture was then filtered and basified withsaturated sodium bicarbonate and partitioned between ethyl acetate andwater. The organic layer was dried with sodium sulfate and concentratedand passed through a plug of silica to yield(4-{2-[(3-amino-4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide.

[0736] MS: MH+=422.1.

[0737] 4. Synthesis of4-[(2-{[4-chloro-3-(2-oxopyrrolidin-1-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide

[0738] To(4-{2-[(3-amino-4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamidein chloroform was added 4-chlorobutanoylchloride (1.5 eq) and sodiumphosphate (3 eq) and stir for 2 hours. Acylation was checked by HPLC/MS.The mixture was partitioned between methylene chloride and water. Theorganic layer was dried with sodium sulfate and concentrated. The crudewas taken in tetrahydrofuran and Potassiumbis(trimethylsilyl)amide ( 2eq) was added to it and the mixture was heated at 100 C for 16 h. Themixture was concentrated and partitioned between ethyl acetate andwater. The organic layer was dried and concentrated to give4-[(2-{[4-chloro-3-(2-oxopyrrolidin-1-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide.

[0739] MS: MH+=490.9.

EXAMPLE 1155 Preparation of4-[(2-{[4-chloro-3-(2-oxopiperidin-1-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide

[0740]

[0741] To(4-{2-[(3-amino-4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamidein chloroform was added 5-bromopentanoylchloride (1.5 eq) and sodiumphosphate (3 eq) and stir for 2 hours. Acylation was checked by HPLC/MS.The mixture was partitioned between methylene chloride and water. Theorganic layer was dried with sodium sulfate and concentrated. The crudeN-acylated product was taken in tetrahydrofuran andPotassiumbis(trimethylsilyl)amide ( 2 eq) was added to it and themixture was heated at 100° C. for 16 h. The mixture was concentrated andpartitioned between ethyl acetate and water. The organic layer was driedand concentrated to give4-[(2-{[4-chloro-3-(2-oxopiperidin-1-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide.

[0742] MS: MH+=504.17.

EXAMPLE 1156 Preparation of4-({2-[(4-tert-butylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide

[0743]

[0744] Step 1: Synthesis of4-[4-(methylamino)-3-nitrophenoxy]pyridine-2-carboxylic acid

[0745] To tert-butyl4-[4-methylamino)-3-nitrophenoxy]pyridine-2-carboxylate was addedtrifluoroacetic acid and the mixture was stirred at ambient temperaturefor 16 h. Formation of4-[4-(methylamino)-3-nitrophenoxy]pyridine-2-carboxylic acid wasobserved by HPLC/MS. The mixture was azeotroped with toluene until itbecame a red solid.

[0746] MS: MH+=289.

[0747] Step 2: Synthesis of4-[4-(methylamino)-3-nitrophenoxy]pyridine-2-carboxamide

[0748] To 4-[4-(methylamino)-3-nitrophenoxy]pyridine carboxylic acid intetrahydro-furan was added EDC (2 eq) and HOAT (1.5 eq) and ammoniumchloride (2 eq). The resulting mixture was stirred at ambienttemperature for 16 h. The mixture was concentrated and partitionedbetween ethylacetate and water. A solid crashes out in the aqueous layerwhich was filtered and was found to be the product on LC/MS. The organiclayer was then dried with sodium sulfate and concentrated. Purificationon silica gel gave4-[4-(methylamino)-3-nitrophenoxy]pyridine-2-carboxamide.

[0749] MS: MH+=288.

[0750] Step 3: Synthesis of4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxamide

[0751] The mixture containing4-[4-(methylamino)-3-nitrophenoxy]pyridine-2-carboxamide in methanolwith catalytic amount of 10% Pd/C was hydrogenated to yield4-(3-amino-4-(methylamino)phenoxy]pyridine-2-carboxamide.

[0752] MS: MH+=258.

[0753] Step 4: Synthesis of4-({2-[(4-tert-butylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide.

[0754] To 4-(tert)-butylbenzeneisothiocyanate (1 eq) in methanol wasadded 4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxamide (1 eq)and stirred at ambient temperature for 16 h. Formation of thiourea wasobserved by LC/MS. To it was then added ferric chloride (1.5 eq ) andstirred at ambient temperature for 4 h. The reaction mixture wasconcentrated and 1M sodium hydroxide was added to neutral pH. Themixture was then partitioned between ethyl acetate and water. Theorganic layer was dried with sodium sulfate and concentrated andpurified on preparative chromatography to give the desired product.

[0755] MS: MH+=415.4.

EXAMPLE 1157 Preparation ofN-methyl-4-[(1-methyl-2-{[3-(2-pyrrolidin-1-ylethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide

[0756]

[0757] Step 1: Synthesis of [2-(3-nitrophenyl)ethyl]pyrrolidine

[0758] To 2-(3-nitrophenyl)ethan-1-ol in methylene chloride at 0° C. wasadded methanesulfonylchloride (2 eq) and pyridine (4 eq) and stirred for30 minutes. The formation of the mesylate was observed on LC/MS. Waterwas then added and the organic layers was separated and washed with 1Mcitric acid. The organic layer was dried with sodium sulfate andconcentrated. To give the mesylate. The mesylate was taken intetrahydrofuran and pyrrolidine (4 eq) was added and the mixture washeated to 80° C. for 16 h. The mixture was concentrated and partitionedbetween ethyl acetate and water. The organic layer was dried with sodiumsulfate and concentrated. It was then passed through a plug of silica toyield [2-(3-nitrophenyl)ethyl]pyrrolidine.

[0759] MS: MH+=220.

[0760] Step 2: Synthesis of 3-(2-pyrrolidinylethyl)phenylamine

[0761] The mixture containing [2-(3-nitrophenyl)ethyl]pyrrolidine inmethanol with catalytic amount of 10% Pd/C was hydrogenated to yield3-(2-pyrrolidinylethyl)phenylamine.

[0762] MS: MH+=190.

[0763] Step 3: Synthesis of 3-(2-pyrrolidinylethyl)benzeneisothiocyanate

[0764] To [2-(3-nitrophenyl)ethyl]pyrrolidine in acetone at 0° C. wasadded sodium bicarbonate (2 eq) and thiophosgene (2 eq). The mixture wasbrought to ambient temperature and concentrated and partitioned betweenethyl acetate and water. The organic layer was dried with sodiumbicarbonate and sodium sulfate and concentrated to yield3-(2-pyrrolidinylethyl)benzeneisothiocyanate.

[0765] MS: MH+=232.

[0766] Step 4: Synthesis ofN-methyl-4-[(1-methyl-2-{[3-(2-pyrrolidin-1-ylethyl)phenyl]-amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide

[0767] To 3-(2-pyrrolidinylethyl)benzeneisothiocyanate (1 eq) inmethanol was added{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1eq) and stirred at ambient temperature for 16 h. The correspondingthiourea formation was followed by LC/MS. To it was the added anhydrousferric chloride (1.5 eq) and stirred at ambient temperature for 2 h. Themixture was concentrated and 1M sodium hydroxide to bring it to neutralpH. It was then extracted with ethyl acetate and the organic layer wasseparated and dries with sodium sulfate and concentrated. Preparativechromatography yieldedN-methyl-4-[(1-methyl-2-{[3-(2-pyrrolidin-1-ylethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide.

[0768] MS: MH+=470.

EXAMPLE 1158 Preparation of 2-fluoropyridin-4-ylboronic acid

[0769]

[0770] The reaction flask was flame dried and cooled under nitrogen. Asolution of 1 (1.0 eq) in THF was added to the reaction flask followedby triisopropyl borate (1.2 eq). The reaction solution was cooled toapproximately −72° C. with a dry ice/acetone bath. N-butyl lithium (1.5eq, 2.5M solution in hexane) was added drop wise over 40 minutes. Thereaction solution was stirred for another 30 minutes at −72° C. Thereaction solution was then warmed to approx. −25° C. with a saturatedNaCl/dry ice bath to stir at and stirred for 20 minutes before 2N HCl(2.0 eq) was added. The reaction solution was then warmed to RT. Theorganic and aqueous layers were separated. The aqueous layer was washedonce with ethyl acetate. The organic layers were combined, dried(Na2SO4), and concentrated under vacuum to yield the desired product 2.MS: MH+=141

EXAMPLE 1158 Preparation of3-Bromo-4-(2,2,2-trifluoro-ethoxy)-phenylamine

[0771]

[0772] 3-Bromo-4-fluoronitrobenzene (1.0 eq) was added to a stirringsolution of 2,2,2-trifluoroethanol (1.1 eq) and potassium carbonate (2.0eq) in DMF. The solution was heated for 18 hours at 90° C. at which timeno starting material was apparent by LCMS. The solution was cooled andfiltered through Celite and the plug washed with EtOAc. The organiclayer is then washed with brine and water, dried over MgSO4, filteredand concentrated to yield the desired product 97% pure, 80% yield. LCRt=2.975 min. MH+=302.0

[0773] 2-Bromo-4-nitro-1-(2,2,2-trifluoro-ethoxy)-benzene was dissolvedin EtOAc, purged with nitrogen, and a catalytic amount of Pd on Carbonadded. The solution is purged a number of times, then left to stirovernight under an atmosphere of nitrogen. The solution is filteredthrough Celite and concentrated yielding the desired product inquantitative yield. LC Rt=1.852 min. MH+=270.0

EXAMPLE 1159 Preparation of 3-Bromo-4-isopropoxy-phenylamine

[0774]

[0775] 3-Bromo-4-fluoronitrobenzene (1.0 eq) was added to a stirringsolution of potassium carbonate (2.0 eq) in isopropanol. The solutionwas heated for 4 days at 80° C. The solution was cooled and filteredthrough Celite and the plug washed with EtOAc. The organic layer is thenwashed with brine and water, dried over MgSO4, filtered and concentratedto yield the desired product. Rt=8.72 min.

[0776] The nitrobenzene was dissolved in EtOAc, purged with nitrogen,and a catalytic amount of Pd on Carbon added. The solution is purged anumber of times, then left to stir overnight under an atmosphere ofnitrogen. The solution is filtered through Celite and concentratedyielding the desired product in quantitative yield. LC Rt=1.71 min.MH+=230.0

EXAMPLE 1160 Preparation of 3-Isopropyl-4-fluoroaniline

[0777]

[0778] (As per WO 97/06136) In a three-necked 250 mL Morton flask withinternal thermometer, addition funnel and stirbar, sulfuric acid (60 mL)was cooled to −10° C. 2′-fluoroacetophenone (17.9 g) was added at such arate as to keep the internal temperature below 0° C. The funnel waswashed down with sulfuric acid (4 mL), and charged with HNO₃ (9.5 mL)).This was added dropwise at such a rate that the internal temperaturenever exceeded 5° C. These additions can be made more quickly if theaddition funnel has an ice-jacket. Stirring continued at −10° C. 30 min.The mixture was then poured onto ice and extracted with ethyl acetate(2×) the combined extracts were washed (H₂O, NaHCO₃, NaCl), dried(K₂CO₃) filtered and stripped to an amber oil 22.3 gm=93.7%

[0779] In a flame dried flask with nitrogen atmosphere and stirbar,KHMDS (11 mL, 0.5M in toluene) was added dropwise over 5 min to astirred suspension of Ph₃P⁺CH₃Br⁻ (2.34 gm) in THF (50 mL, dry) at −78°C. Yellow color appears as the addition proceeds. After 5 min at −78°C., the suspension was stirred at RT (5 min) then recooled to −78° C.The acetophenone (1.00 gm in 10 mL dry THF) was added dropwise over fiveminutes. Deep red color appears as the addition proceeds. Afteradditional 2 min at −78° C., the system was allowed to warm to RT. AfterTLC (17% EtOAc in hexanes) confirmed the consumption of startingmaterials, volatiles were removed and the residue suspended incyclohexane (15 mL). Upon cooling, the solids were filtered off anddiscarded. The filtrate was purified by flash chromatography (30%acetone in hexanes). Hydrogenation of this material over palladium oncarbon (10% w/w) in methanol (RT, 2 hrs) provides3-isopropyl-4-fluoroaniline (quantitative).

EXAMPLE 1161 Preparation of 4-Methyl-3-(3-furyl)-nitrobenzene

[0780]

[0781] A suspension of 3-bromo-4-methyl nitrobenzene 1 (421 mg, 2.0mmol), 3-furan boronic acid 2 (452 mg, 4.0 mmol), diisopropylethylamine(1.4 mL, 8.0 mmol), and Pd(dppf)Cl₂—CH₂Cl₂ (162 mg, 0.2 mmol) in dry NMP(10 mL) was sparged with Ar for 20 min. The reaction mixture was heatedto 80° C. and maintained at that temperature for 16 h. The reaction wasallowed to cool to rt and was then partitioned with water and EtOAc. Theresulting mixture was filtered through Celite and the phases partitionedand separated. The aqueous portion was extracted with EtOAc (3×) and thecombined organic phases were washed with brine, dried (MgSO₄), andconcentrated. The crude residue was adsorbed onto SiO₂ and purified byflash chromatography (9:1 hexanes-EtOAc) to furnish 319 mg (1.57 mmol,80%) of an off-white solid as 3: ¹H NMR (300 MHz, CD₃OD) δ 8.16 (d,J=2.5 Hz, 1 H), 8.04 (dd, J=2.5, 8.5 Hz, 1 H), 7.77 (dd, J=0.8, 1.7 Hz,1 H), 7.63 (app t, J=1.9 Hz, 1 H), 7.48 (d, J=8.5 Hz, 1 H), 6.72 (dd,J=0.8, 1.9 Hz, 1 H), 2.48 (s, 3H).

EXAMPLE 1162 Preparation of 4-Methyl-3-(3-furyl)-aniline

[0782]

[0783] A suspension of 4-methyl-3-(3-furyl) nitrobenzene 1 (91 mg, 0.45mmol) and Lindlar's catalyst (0.2mmol) in methanol was placed under anH₂ atmosphere and the resulting reaction was maintained overnight at rt.The reaction mixture was filtered through Celite and the remainingsolids were washed with EtOAc. The combined organic portions wereconcentrated to provide 74 mg (0.43 mmol, 96%) of an amber residue as 2:¹H NMR (300 MHz, CD₃OD) δ 7.56 (app t, J=1.1 Hz, 1 H), 7.52 (dd, J=1.7,1.9 Hz, 1 H), 6.97 (d, J=8.0 Hz, 1 H), 6.75 (d, J=2.5 Hz, 1 H), 6.60 (m,2 H), 2.23 (s, 3 H).

EXAMPLE 1163 Preparation of 4-Methyl-3-(3-tetrahydrofuryl)-aniline

[0784]

[0785] A suspension of 4-methyl-3-(3-furyl) nitrobenzene 1 (470 mg, 2.31mmol) and 10% Pd/C (245 mg, 0.23 mmol) in methanol (10 mL) was placedunder an H₂ atmosphere and the resulting reaction was maintainedovernight at rt. The reaction mixture was filtered through Celite andthe remaining solids were washed with EtOAc. The combined organicportions were concentrated to provide 400 mg (2.26 mmol, 98%) of anamber residue as 2: LCMS m/z 178.2 (MH³⁰ ), t_(R)=1.53 min.

[0786] Examples 1164-1400 in Table 16 below were prepared according tothe procedures and examples above. TABLE 16 Example Structure Name MH+1164

4-({2-[(3-bromo-4-fluorophenyl)amino]- 1-methyl-iH-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 471.3 1165

4-[(2-{[4-fluoro-3-(2-fluoropyridin-4- yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 487.5 1166

4-[(2-{[4-fluoro-3-(6-methoxypyridin-3- yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 499.5 1167

4-[(2-{[4-fluoro-3-(4-methylpyridin-3-yl)phenylljamino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-methylpyridine-2- carboxamide 483.5 1168

4-[(2-{[4-chloro-3-(5-methoxypyridin-3- yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 551.9 1169

4-[(2-{[4-chloro-3-(2,6-dimethylpyridin-3-yl)phenyl]amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-methylpyridine-2- carboxamide 513.9 1170

4-[(2-{[4-chloro-3-(4-methylpyridin-3- yl)phenylllamino}-1-methyl-1H-benz- imidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide 499.9 1171

4-[(2-{[4-chloro-3-(2-methylpyridin-4- yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 499.9 1172

4-[(2-{[3-fluoro-2-methoxy-5-(5-meth- oxypyridin-3-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 529.51173

4-[(2-{[3-fluoro-2-methoxy-5-(6- methoxypyridin-3-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 529.51174

4-{[2-({3-fluoro-2-methoxy-5-[6-(1H-pyrrol-1-yl)pyridin-3-yl]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N- methylpyridine-2-carboxamide 564.61175

4-[(2-{[3-fluoro-2-methoxy-5-(2-methyl-pyridin-4-yl)phenyl]amino}-1-methyl- 1H-benzimidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide 513.5 1176

4-[(2-{[5-(2,6-dimethylpyridin-3-yl)-3- fluoro-2-methoxyphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 527.61177

4-[(2-{[5-(2-chloropyridin-3-yl)-3- fluoro-2-methoxyphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oyx]-N- methylpyridine-2-carboxamide 533.91178

4-[(2-{[3-fluoro-5-(2-fluoropyridin-4-yl)-2-methoxyphenyl]amino}-1-methyl- 1H-benzimidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide 517.5 1179

4-[(2-{[3-fluoro-2-methoxy-5-(4-methyl-pyridin-3-yl)phenylllamino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 513.5 1180

4-[(2-{[3-fluoro-5-(6-fluoropyridin-3-yl)-2-methoxyphenyl]amino}-1-methyl- 1H-benzimidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide 517.5 1181

N-methyl-4-({1-methyl-2-[(4-pyridin-2-yl-1,3-thiazol-2-yl)amino]-1H-benz- imidazol-5-yl}oxy)pyridine-2-carbox-amide 458.5 1182

4-({2-[(2-methoxy-5-quinolin-3-yl- phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 531.6 1183

4-[(2-{[2-methoxy-5-(6-methoxypyridin- 3-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 511.6 1184

4-[(2-{[5-(2,6-dimethylpyridin-3-yl)-2-methoxyphenyl]amino}-1-methyl-1H- benzimidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide 509.6 1185

4-[(2-{[5-(3-fluoropyridin-4-yl)-2-meth-oxyphenyl]amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-methylpyridine-2- carboxamide 499.5 1186

4-[(2-{[5-(2-fluoropyridin-4-yl)-2-meth-oxyphenyl]amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-methylpyridine-2- carboxamide 499.5 1187

4-({2-[(5-isoquinolin-4-yl-2-methoxy- phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 499.5 1188

4-({2-[(3-bromo-4-chlorophenyl)amino]-1-methyl-1H-benzirnidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide487.1 1189

4-({2-[(4-chloro-3-pyridin-4-ylphenyl)-amino]-1-methyl-1H-benzimidazol-5- yl}oxy)-N-(2-pyrrolidin-1-ylethyl)-pyridine-2-carboxamide 568.2 1190

4-({2-[(4-chloro-3-pyridin-3-ylphenyl)-amino]-1-methyl-1H-benzimidazol-5- yl}oxy)-N-(2-pyrrolidin-1-ylethyl)-pyridine-2-carboxamide 568.3 1191

4-[(2-{[4-chloro-3-(2-fluoropyridin-4-yl)phenyl]amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-(2-pyrrolidin-1-yl- ethyl)pyridine-2-carboxamide586.2 1192

4-[(2-{[4-chloro-3-(6-methoxypyridin-3-yl)phenyl]amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-(2-pyrrolidin-1-yl- ethyl)pyridine-2-carboxamide598.3 1193

N-methoxy-4-{[1-methyl-2-({4-[(tri- fluoromethyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2- carboxamide 490.1 1194

4-[(2-{[3-bromo-4-(2,2,2-trifluoro- ethoxy)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 551.0 1195

4-[(2-{[3-(6-fluoropyridin-3-yl)-4-(2,2,2-trifluoroethoxy)phenyl]amino}-1-methyl-lH-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 567.31196

N-methyl-4-[(1-methyl-2-{[3-pyridin-4-yl-4-(2,2,2-trifluoroethoxy)phenyl]- amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 549.3 1197

4-[(2-{[3-(6-methoxypyridin-3-yl)-4-(2,2,2-trifluoroethoxy)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 579.31198

N-methyl-4-[(1-methyl-2-{[3-(2-methyl-pyridin-4-yl)-4-(2,2,2-trifluoroethoxy)-phenyl]amino}-1H-benzimidazol-5-yl)- oxy]pyridine-2-carboxamide 563.31199

4-[(2-{[3-isoquinolin-4-yl-4-(2,2,2-tri-fluoroethoxy)phenyl]amino}-1-methyl- 1H-benzimidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide 599.3 1200

4-({2-[(4-chloro-3-thien-3-ylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-pyrrolidin-1-ylethyl)- pyridine-2-carboxamide 573.3 1201

N-methyl-4-[(1-methyl-2-{[3-quinolin-3-yl-4-(2,2,2-trifluoroethoxy)phenyl]- amino}-1H-benzimidazoi-5-yl)oxy]-pyridine-2-carboxamide 599.3 1202

N-methyl-4-[(1-methyl-2-{[3-(4-methyl-pyridin~3-yi)-4-(2,2,2-trifluoroethoxy)-phenyl]amino}-1H-benzimidazol-5-yl)- oxy]pyridine-2-carboxamide 563.31203

4-[(2-{[3-(5-methoxypyridin-3-yl)-4-(2,2,2-trifluoroethoxy)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 579.31204

N-methyl-4-[(1-methyl-2-{[3-[5-(1H-pyrrol-1-yl)pyridin-3-yl]-4-(2,2,2-tri-fluoroethoxy)phenyl]amino}-1H-benz- imidazol-5-yl)oxy]pyridine-2-carbox-amide 614.3 1205

4-[(2-{[3-(2,6-dimethylpyridin-3-yl)-4-(2,2,2-trifluoroethoxy)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 577.31206

N-methyl-4-[(1-methyl-2-{[3-(5-methyl- 2-furyl)-4-(2,2,2-trifluoroethoxy)phenyl]amino}-1H- benzimidazol-5-yl)oxy]pyridine-2-carboxamide 552.2 1207

N-methyl-4-[(1-methyl-2-{[3-thien-3-yl-4-(2,2,2-trifluoroethoxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2- carboxamide 554.2 1208

N-methyl-4-[(1-methyl-2-{[3-thien-2-yl-4-(2,2,2-trifluoroethoxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyr1dine-2- carboxamide 554.3 1209

N-methyl-4-[(1-methyl-2-{[3-pyridin-3-yl-4-(2,2,2-trifluoroethoxy)phenyl]- amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 549.3 1210

N-methoxy-4-{[1-methyl-2-({3-[(tri- fluoromethyl)thiolphenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2- carboxamide 490.1 1211

N-methoxy-4-[(1-methyl-2-{[3-{[tri- fluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2- carboxamide 474.1 1212

N-methoxy-4-[(1-methyl-2-{[4-(tri- fluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2- carboximide 474.1 1213

N-(allyloxy)-4-[(1-methyl-2-{[3-(tri-fluoromethoxy)phenyl]amino}-1H-benz-imidazol-5-yl)oxy]pyridine-2-carbox- amide 500.1 1214

N-(allyloxy)-4-[(1-methyl-2-{[4-(tri- fluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2- carboxamide 500.1 1215

N-(allyloxy)-4-{[1-methyl-2-({3-[(tri-fluoromethyl)thio]phenyl}amino)-1H- benzimidazol-5-yl]oxy}pyridine-2-carboxamide 516.1 1216

N-(allyloxy)-4-{[1-methyl-2-({4- [(trifluoromethyl)thiolphenyl}amino)-1H-benzimidzo1-5-yyl]oxy}pyridine-2- carboxamide 516.1 1217

N-ethoxy-4-[(1-methyl-2-{[4-(tri- fluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2- carboxamide 488.3 1218

N-ethoxy-4-{[1-methyl-2-({3-[(tri- fluoromethyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2- carboxamide 504.3 1219

N-ethoxy-4-{[1-methyl-2-({4- [(trifluoromethyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2- carboxamide 504.2 1220

N-(tert-butoxy)-4-[(1-methyl-2-{[4-(tri-fluoromethoxy)phenyl]amino}-1H-benz-imidazol-5-yl)oxy]pyridine-2-carbox- amide 516.3 1221

N-(tert-butoxy)-4-{[1-methyl-2-({3-[(trifluoromethyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2- carboxamide 532.3 1222

N-(tert-butoxy)-4-{[1-methyl-2-({4-[(trifluoromethyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2- carboxamide 532.3 1223

N-(benzyloxy)-4-{[1-methyl-2-({3- [(trifluoromethyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2- carboxamide 566.3 1224

N-(benzyloxy)-4-{[1-methyl-2-({4- [(trifluoromethyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2- carboxamide 566.2 1225

4-{[1-methyl-2-({3-[(trifluoromethyl)-thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}-N-phenoxypyridine-2-carbox- amide 552.3 1226

4-{[1-methyl-2-({4-[(trifluoromethyl)-thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}-N-phenoxypyridine-2-carbox- amide 552.3 1227

4-({2-[(4-fluoro-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methoxypyridine-2-carbox- amide 450.3 1228

4-({2-[(3-cyclopentylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methoxypyridine-2-carboxamide 458.41229

N-methoxy-4-({1-methyl-2-[(3-pyridin-4-ylphenyl)amino]-1H-benzimidazol-5- yl}oxy)pyridine-2-carboxamide 467.31230

4-({2-[(3-cyclopentyl-4- fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methoxypyridine-2-carboxamide 476.3 1231

4-[(2-{[3-(2,2-dichloro-1- methylcyclopropyl)-4-methylphenyl]amino}-1-methyl-1H- benzimidazol-5-yl)oxy]-N-methoxypyridine-2-carboxamide 526.2 1232

1-({2-[(3-isopropyl-4- methylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methoxypyridine-2-carboxamide 446.3 1233

4-({2-[(3-sec-butylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-methoxypyridine-2-carboxamide 446.3 1234

4-({2-[(3-tert-butylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-methoxypyridine-2-carboxamide 446.3 1235

4-({2-[(4-ethyl-3- isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methoxypyridine-2-carboxamide 460.4 1236

4-({2-[(4-tert-butylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-methoxypyridine-2-carboxamide 446.3 1237

4-[(2-{[2-fluoro-5-(trifluoromethyl)- phenyl]amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-methoxypyridine- 2-carboxamide 476.2 1238

4-({2-[(4-bromophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-methoxypyridine-2-carboxamide 468.2 1239

N-ethoxy-4-({1-methyl-2-[(3-pyridin-4-ylphenyl)amino]-1H-benzimidazol-5- yl}oxy)pyridine-2-carboxamide 481.41240

N-(allyloxy)-4-({1-methyl-2-[(3-pyridin-4-ylphenyl)amino]-1H-benzimidazol-5- yl}oxy)pyridine-2-carboxamide 493.31241

N-(tert-butoxy)-4-({1-methyl-2-[(3- pyridin-4-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2- carboxamide 509.4 1242

4-{1-methyl-2-[(3-pyridin-4-ylphenyl)-amino]-1H-benzimidazol-5-yl}oxy)-N- phenoxypyridine-2-carboxamide 529.31243

N-(benzyloxy)-4-({1-methyl-2-[(3- pyridin-4-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2- carboxamide 543.3 1244

N-isobutoxy-4-{[1-methyl-2-({3- [(trifluoromethyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2- carboxamide 532.1 1245

N-isobutoxy-4-{[1-methyl-2-({4- [(trifluoromethyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2- carboxamide 532.1 1246

4-({2-[(4-isopropoxy-3-pyridin-4-yl- phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 509.4 1247

4-({2-[(4-isopropoxy-3-pyridin-3-yl- phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 509.4 1248

4-[(2-{[3-(6-fluoropyridin-3-yl)-4- isopropoxyphenyl]amino]56-1-methyl-1H- benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide527.4 1249

4-({2-[(4-isopropoxy-3-quinolin-3-yl- phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 559.4 1250

4-({2-[(4-isopropoxy-3-thien-2- ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 514.3 1251

4-({2-[(4-isopropoxy-3-thien-3-yl- phenyi)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 514.3 1252

4-[(2-{[4-isopropoxy-3-(4-methyl- pyridin-3-yl)phenyl]amino]56-1-methyl- 1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide523.4 1253

4-[(2-{[4-isopropoxy-3-(5- methoxypyridin-3-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 539.41254

4-[(2-{[4-isopropoxy-3-(6-methoxy- pyridin-3-yl)phenyl]amino]56-1-methyl- 1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide539.5 1255

4-({2-[(3-cyclopentyl-4-methylphenyl)-amino]-1-methyl-1H-benzimidazol-5- yl}oxy)-N-(2-hydroxyethyl)pyridine-2-carboxamide 486.6 1256

4-({2-[(3-cyclopentyl-4-methylphenyl)-amino]-1-methyl-1H-benzimidazol-5- yl}oxy)-N-{2-[(methylsulfonyl)amino]-ethyl}pyridine-2-carboxamide 563.7 1257

4-({2-[(3-cyclopentyl-4-methylphenyl)-amino]-1-methyl-1H-benzimidazol-5- yl}oxy)pyridine-2-carboxamide 442.51258

4-({2-[(3-cyclopentyl-4-methylphenyl)-amino]-1-methyl-1H-benzimidazol-5- yl}oxy)-N-methylpyridine-2-carbox-amide 456.5 1259

4-({2-[(3-cyclopentyl-4-methylphenyl)-amino]-1-methyl-1H-benzimidazol-5- yl}oxy)-N-(1-isopropylazetidin-3-yl)-pyridine-2-carboxamide 539.7 1260

4-({2-[(3-cyclopentyl-4-fluorophenyl)-amino]-1-methyl-1H-benzimidazol-5- yl}oxy)-N-(2-hydroxyethyl)pyridine-2-carboxamide 490.5 1261

4-({2-[(3-cyclopentyl-4-fluorophenyl)-amino]-1-methyl-1H-benzimidazol-5- yl}oxy)-N-{2-[(isopropylsulfonyl)-amino]ethyl}pyridine-2-carboxamide 595.7 1262

4-{2-[(3-cyclopentyl-4-fluorophenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carbox- amide 460.5 1263

4-{2-[(3-cyclopentyl-4-fluorophenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(1-isopropylazetidin-3-yl)- pyridine-2-carboxamide 543.7 1264

4-{2-[(3-cyclopentyl-4-fluorophenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(2-oxopyrrolidin-1-yl)- propyl]pyridine-2-carboxamide 571.71265

4-({2-[(3-cyclopentyl-4-fluorophenyl)-amino]-1-methyl-1H-benzimidazol-5- yl}oxy)-N-{2-[(methylsulfonyl)amino]-ethyl}pyridine-2-carboxamide 567.7 1266

4-({2-[(3-cyclopentyl-4-fluorophenyl)-amino]-1-methyl-1H-benzimidazol-5- yl}oxy)-N-(2-{[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino]}ethyl)pyridine-2- carboxamide 633.7 1267

4-({2-[(3-cyclopentyl-4-fluorophenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(1-isopropylpiperidin-4-yl)- pyridine-2-carboxamide 571.7 1268

4-({2-[(3-cyclopentyl-4-fluorophenyl)-amino]-1-methyl-1H-benzimidazol-5- yl}oxy)pyridine-2-carboxamide 446.51269

4-({2-[(3-isopropyl-4-methylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carbox- amide 430.5 1270

N-(1-isopropylazetidin-3-yl)-4-({2-[(3-isopropyl-4-methylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide 513.7 1271

4-({2-[(3-isopropyl-4-methylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(2-oxopyrrolidin-1-yl)- propyl]pyridine-2-carboxamide 541.71272

4-({2-[(3-isopropyl-4-methylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-pyrroiidin-1-ylethyl)- pyridine-2-carboxamide 513.7 1273

4-({2-[(3-isopropyl-4-methylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(4-methylpiperazin-1-yl)- ethyl]pyridine-2-carboxamide542.7 1274

4-({2-[(3-isopropyl-4-methylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-morpholin-4-ylethyl)- pyridine-2-carboxamide 529.7 1275

N-[2-(acetylamino)ethyl]-4-({2-[(3-iso- propyl-4-methylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 501.6 1276

4-({2-[(3-isopropyl-4-methylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-{2-[(isopropylsulfonyl)- amino]ethyl}pyridine-2-carboxamide565.7 1277

N-(2-hydroxyethyl)-4-({2-[(3-isopropyl-4-methylphenyl)amino]-1-methyl-1H- benzimidazol-5-yl}oxy)pyridine-2-carboxamide 460.5 1278

4-({2-[(3-isopropyl-4-methylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-methoxyethyl)pyridine-2- carboxamide 474.6 1279

4-({2-[(3-isopropyl-4-methylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(4-methyipiperazin-1-yl)- propyl]pyridine-2-carboxamide556.7 1280

N-[3-(1H-imidazol-1-yl)propyl]-4-({2-[(3-isopropyl-4-methylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide 524.6 1281

4-({2-[(3-isopropyl-4-methylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(2-oxoimidazolidin-1-yl)- ethyl]pyridine-2-carboxamide528.6 1282

-({2-[(3-isopropyl-4-methylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide 416.5 1283

4-({2-[(4-ethyl-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carbox- amide 444.5 1284

4-({2-[(4-ethyl-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(1-isopropylazetidin-3-yl)- pyridine-2-carboxamide 527.7 1285

4-({2-[(4-ethyl-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(2-oxopyrrolidin-1- yl)propyl]pyridine-2-carboxamide 555.71286

4-({2-{(4-ethyl-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-pyrrolidin-1-ylethyl)- pyridine-2-carboxamide 527.7 1287

4-({2-[(4-ethyl-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(4-methylpiperazin-1-yl)- ethyl]pyridine-2-carboxamide556.7 1288

4-({2-[(4-ethyl-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-morpholin-4-ylethyl)- pyridine-2-carboxamide 543.7 1289

N-[2-(acetylamino)ethyl]-4-({2-[(4- ethyl-3-isopropyiphenyl) amino]-1-methyl-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 515.6 1290

4-({2-[(4-ethyl-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-{2-[(isopropylsulfonyl)- amino]ethyl}pyridine-2-carboxamide579.7 1291

4-({2-[(4-ethyl-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-hydroxyethyl)pyridine-2- carboxamide 474.6 1292

4-({2-[(4-ethyl-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-methoxyethyl)pyridine-2- carboxamide 488.6 1293

4-{2-[(4-ethyl-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(4-methylpiperazin-1-yl)- propyl]pyridine-2-carboxamide570.8 1294

4-({2-[(4-ethyl-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3 -(1H-imidazol-1-yl)- propyl]pyridine-2-carboxamide 538.71295

4-({2-[(4-ethyl-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(2-oxoimidazolidinl-1-yl)- ethyl]pyridine-2-carboxamide542.7 1296

4-({2-[(4-fluoro-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methoxypyridine-2-carbox- amide 450.5 1297

4-({2-[(4-fluoro-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carbox- amide 434.5 1298

4-({2-[(4-fluoro-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(1-isopropylpiperidin-4-yl)- pyridine-2-carboxamide 545.7 1299

4({2-[(4-fluoro-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(1-isopropylazetidin-3-yl)- pyridine-2-carboxamide 517.6 1300

4-({2-[(4-fluoro-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3 -(2-oxopyrrolidin-1-yl)- propyl]pyridmne-2-carboxamide545.6 1301

4-({2-[(4-fluoro-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-pyrrolidin-1-ylethyl)- pyridine-2-carboxamide 517.6 1302

4-({2-[(4-fluoro-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(4-methylpiperazin-1-yl)- ethyl]pyridine-2-carboxamide546.7 1303

4-({2-[(4-fluoro-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-morpholin-4-ylethyl)- pyridine-2-carboxamide 533.6 1304

4-({2-[(4-fluoro-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-{2-[(isopropylsulfonyl)- amino]ethyl}pyridine-2-carboxamide569.7 1305

4-( {2-[(4-fluoro-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-hydroxyethyl)pyridine-2- carboxamide 464.5 1306

4-({2-[(4-fluoro-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-methoxyethyl)pyridine-2- carboxamide 478.5 1307

4-({2-[(4-fluoro-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(4-methylpiperazin-1-yl)- propyl]pyridine-2-carboxamide560.7 1308

4-({2-[(4-fluoro-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(1H-imidazol-1-yl)- propyl]pyridine-2-carboxamide 528.61309

4-({2-[(4-fluoro-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(2-oxoimidazolidin-1-yl)- ethyl]pyridine-2-carboxamide532.6 1310

4-({2-[(4-fluoro-3-isopropylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide 420.5 1311

4-[(2-{[3-isopropyl-4-(trifluoro- methoxy)phenyl]amino]}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 500.5 1312

N-(1-isopropylazetidin-3-yl)-4-[(2-{[3-isopropyl-4-(trifluoromethoxy)phenyl]-amino}-1-methyl-1H-benzimidazol-5- yl)oxy]pyridine-2-carboxamide 583.61313

4-[(2-{[3-isopropyl-4-(trifluoro- methoxy)phenyl]amino]56 -1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(2-oxo- pyrrolidin-1-yl)propyl]pyridine-2-carboxamide 611.6 1314

4-[(2-{[3-isopropyl-4-(trifluoro- methoxy)phenyl]amino]56 -1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-pyrrolidin- 1-ylethyl)pyridine-2-carboxamide583.6 1315

4-[(2-{[3-isopropyl-4-(trifluoro- methoxy)phenyl]amino]56 -1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(4-methyl-piperazin-1-yl)ethyl]pyridine-2-carbox- amide 612.7 1316

N-[2-(acetylamino)ethyl]-4-[(2-{[3-isopropyl-4-(trifluoromethoxy)phenyl]-amino}-1-methyl-1H-benzimidazol-5- yl)oxy]pyridine-2-carboxamide 571.61317

N-{2-[(isopropylsulfonyl)amino]ethyl}- 4-[(2-{[3-isopropyl-4-(trifluoro-methoxy)phenyl]amino]56 -1-methyl-1H- benzimidazol-5-yl)oxy]pyridine-2-carboxamide 635.7 1318

N-(2-hydroxyethyl)-4-[(2-{[3-isopropyl-4-(trifluoromethoxy)phenyl]amino}-1- methyl-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 530.5 1319

4-[(2-{[3-isopropyl-4-(trifluoro- methoxy)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-methoxy- ethyl)pyridine-2-carboxamide 544.51320

4-[(2-{[3-isopropyl-4-(trifluoro- methoxy)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(4-methyl-piperazin-1-yl)propyl]pyridine-2-carbox- amide 626.7 1321

4-[(2-{[3-isopropyl-4-(trifluorometh-oxy)phenyl]amino}-1-methyl-1H-benz- imidazol-5-yl)oxy]-N-[2-(2-oxo-imidazolidin-1 -yl)ethyl]pyridine-2- carboxamide 598.6 1322

4-[(2-{[3-(2-methoxypyridin-4-yl)-4- methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 495.6 1323

4-({2-[(3-isopropylphenyl)amino]-1,3- benzoxazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide 403.5 1324

N-methyl-4-({2-[(4-methyl-3-pyridin-3-ylphenyl)amino]-1H-benzimidazol-5- yl}oxy)pyridine-2-carboxamide 451.51325

4-({6-methoxy-1-methyl-2-[(4-methyl-3-pyridin-3-ylphenyl)amino]-1H-benz-imidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 495.6 1326

4-{[2-({3-[2-(ethylamino)pyridin-4-yl]-4-methylphenyl}amino)-1-methyl-1H- benzimidazol-5-yl]oxy}-N-methyl-pyridine-2-carboxamide 508.6 1327

4-[(2-{[3-(2-fluoropyridin-3-yl)-4- methylphenyllamino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 483.5 1328

4-[(2-{[3-(2-fluoropyridin-3-yl)-4- methylphenyilamino}-1H-benzimidazol- 5-yl)oxy]-N-methyipyridine-2-carbox- amide 469.51329

4-[(2-{[3-(2-fluoropyridin-3-yl)-4- methylphenyl]amino}-6-methoxy-1-methyl-1H-benzimidazol-5-yl)oxy]-N- methylpyridine-2-carboxamide 513.51330

N-methyl-4-[(2-{[3-(2-pyrrolidin-1-yl-ethyl)phenyl]amino}-1H-benzimidazol- 5-yl)oxy]pyridine-2-carboxamide457.5 1331

4-[(6-methoxy-1-methyl-2-{[3-(2- pyrrolidin-1-ylethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 501.6 1332

N-methyl-4-[(2-{[3-(2-morpholin-4- ylethyl)phenyl]amino}-1H-benz-imidazol-5-yl)oxy]pyridine-2-carbox- amide 473.5 1333

N-methyl-4-methyl-[(1-methyl-2-{[3-(2-morpholin-4-ylethyl)phenyl]amino}-1H- benzimidazol-5-yl)oxy]pyridine-2-carboxamide 487.6 1334

4-[(6-methoxy-1-methyl-2-{[3-(2- morpholin-4-ylethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 517.6 1335

N-methyl-4-{(2-{[3-(2-piperidin-1-yl-ethyl)phenyl]amino}-1H-benzimidazol- 5-yl)oxy]pyridine-2-carboxamide517.6 1336

N-methyl-4-[(1-methyl-2-{[3-(2- piperidin-1-ylethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2- carboxamide 485.6 1337

4-[(6-methoxy-1-methyl-2-{[3-(2- piperidin-1-ylethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methyl- pyridine-2-carboxamide 515.6 1338

N-(1-isopropylazetidin-3-yl)-4-({1-methyl-2-[(3-pyridin-4-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2- carboxamide 534.6 1339

N-(1-methylpiperidin-4-yl)-4-({1-methyl-2-[(3-pyridin-4-ylphenyl)amino}-1H-benzimidazol-5-yl}oxy)pyridine-2- carboxamide 534.6 1340

N-[2-(2,6-dimethylpiperidin-1-yl)ethyl]-4-({1-methyl-2-[(3-pyridin-4-ylphenyl)-amino]-1H-benzimidazol-5-yl}oxy)- pyridine-2-carboxamide 576.7 1341

4-({2-[(3-tert-butylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-(1-methylpiperidin-4-yl)pyridine-2- carboxamide 513.7 1342

4-({2-[(3-tert-butylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(2,6-dimethylpiperidin-1-yl)ethyl]- pyridine-2-carboxamide 555.7 1343

4-({2-[(3-tert-butylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-(1-isopropylpiperidin-4-yl)pyridine-2- carboxamide 541.7 1344

N-(1-isopropylpiperidin-4-yl)-4-({1-methyl-2-[(3-pyridin-4-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2- carboxamide 562.7 1345

4-({2-[(4-fluoro-3-pyrrolin-1-yl- phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methylpyridine-2- carboxamide 461.5 1346

N-methyl-4-[(1-methyl-2-{[3-(1-methyl- 1H-pyrazol-3-yl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2- carboxamide 454.5 1347

4-({2-[(3-bromo-4-tert-butylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carbox- amide 509.4 1348

N-methyl-4-[(1-methyl-2-{[3-(1H- pyrazol-3-yl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2- carboxamide 440.5 1349

4-({2-[(4-bromo-3-tert-butylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carbox- amide 509.4 1350

4-({2-[(4-bromophenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(2,6-dimethylpiperidin-1-yl)ethyl]- pyridine-2-carboxamide 578.5 1351

N-(1-methyipiperidin-4-yl)-4-[(1- methyl-2-{[4-(trifluoromethyl)phenyl]-amino}-1H-benzimidazol-5-yl)oxy]- pyridine-2-carboxamide 525.5 1352

N-(1-isopropylpiperidin-4-yl)-4-[(1-methyl-2-{[4-(trifluoromethyl)phenyl]- amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide 553.6 1353

N-(1-isopropylazetidin-3-yl)-4-[(1-methyi-2-{[4-(trifluoromethyl)phenyl]- amino}-1H-benzimidazol-5-yl)oxy]-pyrldine-2-carboxamide 525.5 1354

N-[2-(2,6-dimethylpiperidin-1-yl)ethyl]-4-[(1-methyl-2-{[4-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)- oxy]pyrldine-2-carboxamide 567.61355

4-[(1-methyl-2-{[4-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)- oxy]pyrldine-2-carboxamide 428.41356

4-({2-[(3-isopropylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide 402.5 1357

N-[2-(2,6-dimethylpiperidin-1-yl)ethyl]-4-[(2-{[3-(2-fluoropyridin-4-yl)-4- methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridine-2- carboxamide 608.7 1358

4-[(2-{[3-(2-fluoropyridin-4-yl)-4- methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridine-2- carboxamide 469.5 1359

4-[(2-{[4-chloro-3-(2-fluoropyridin-3-yl)phenyl]amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-methylpyrldine-2- carboxamide 503.9 1360

N-methyl-4-[(1-methyl-2-{[3-pyridin-3-yl-4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2- carboxamide 535.5 1361

4-[(2-{[3-(acetylamino)-4-chloro- phenyl]amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-methylpyridine-2- carboxamide 465.9 1362

4-({2-[(4-bromo-3-tert-butylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(1-isopropylazetidin-3-yl)- pyridine-2-carboxamide 592.6 1363

4-({2-[(4-bromo-3-tert-butylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(1-methylpiperidin-4-yl)- pyridine-2-carboxamide 592.6 1364

4-({2-[(4-bromo-3-tert-butylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(2,6-dimethylpiperidin-1- yl)ethyl]pyridine-2-carboxamide634.6 1365

4-({2-[(3-tert-butylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide 416.5 1366

4-[(2-{[2-fluoro-5-(trifluoromethyl)- phenyl]amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]pyridine-2-carbox- amide 446.4 1367

4-[(2-{[2-chloro-5-(trifluoromethyl)- phenyl]amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]pyridine-2-carbox- amide 462.8 1368

4-({2-[(4-ethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2- carboxamide 388.4 1369

4-{[1-methyl-2-({3-[(trifluoromethyl)-thio]phenyl}amino)-1H-benzimidazol-5- yl]oxy}pyridine-2-carboxamide460.5 1370

4-({2-[(4-isopropylphenyl)amino]-1- methyl-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide 402.5 1371

4-({2-[(4-isopropyl-3-methylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carbox- amide 430.5 1372

4-({2-[(4-isopropyl-3-methylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide 416.5 1373

4-({2-[(3-tert-butyl-4-chlorophenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide 450.9 1374

4-({2-[(4-bromo-3-tert-butylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide 495.4 1375

4-({1-ethyl-2-[(3-pyridin-4-ylphenyl)-amino]-1H-benzimidazol-5-yl}oxy)-N- methylpyridine-2-carboxamide 465.51376

4-[(1-ethyl-2-{[3-(2-fluoropyridin-4-yl)-phenyl]amino}-1H-benzimidazol-5-yl)- oxy]-N-methylpyridine-2-carboxamide483.5 1377

4-[(1-ethyl-2-{[3-(2-methoxypyridin-4-yl)-4-methylphenyl]amino}-1H-benz-imidazol-5-yl)oxy]-N-methylpyridine-2- carboxamide 509.6 1378

4-({2-[(4-chloro-3-pyridin-4-ylphenyl)-amino]-1-ethyl-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide 500.0 1379

4-({1-methyl-2-[3-pyridin-4-ylphenyl)- amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide 437.5 1380

4-({2-[(4-chloro-3-pyridin-4-ylphenyl)-amino]-1-methyl-1H-benzimidazol-5- yl}oxy)pyridine-2-carboxamide 471.91381

4-({2-[(4-chloro-3-thien-3-ylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carbox- amide 491.0 1382

4-({2-[(4-chloro-3-thien-2-ylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carbox- amide 491.0 1383

4-({1-methyl-2-[(4-methyl-3-thien-2-yl-phenyl)amino]-1H-benzimidazol-5-yl}- oxy)-N-( 1methylpiperidin-4-yl)-pyridine-2-carboxamide 553.7 1384

N-[2-(2,6-dimethylpiperidin-1-yl)ethyl]-4-({1-methyl-2-[(4-methyl-3-thien-2-yl-phenyl)amino]-1H-benzimidazol-5-yl}- oxy)pyridine-2-carboxamide 595.81385

4-({1-methyl-2-[(4-methyl-3-pyridin-3-ylphenyl)amino]-1H-benzimidazol-5- yl}oxy)pyridine-2-carboxamide 451.51386

4-({2-[(4-chloro-3-thien-2-ylphenyl)- amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide 477.0 1387

4-[(2-{[3-(2-methoxypyridin-4-yl)-4- methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridine-2- carboxamide 481.5 1388

4-({1-methyl-2-[(4-methyl-3-thien-2-yl-phenyl)amino]-1H-benzimidazol-5-yl}- oxy)pyridine-2-carboxamide 456.51389

4-[(2-{[4-bromo-2-(trifluoromethoxy)- phenyl]amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]pyridine-2-carbox- amide 523.3 1390

4-({2-[(3-ethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2- carboxamide 388.4 1391

N-1H-imidazol-2-yl-4-({2-[(3-isopropyl- phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)pyridine-2-carbox- amide 468.3 1392

4-[(2-{[4-chloro-2-(trifluoromethoxy)- phenyl]amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-methylpyridine-2- carboxamide 492.2 1393

4-[(2-{[3-(3-furyl)-4-methylphenyl]- amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carbox- amide 454.3 1394

N-methyl-4-({1-methyl-2-[(4-methyl-3-tetrahydrofuran-3-ylphenyl)amino]-1H- benzimidazol-5-yl}oxy)pyridine-2-carboxamide 458.3 1395

N-methyl-4-({1-methyl-2-[(4-methyl-3-tetrahydrofuran-2-ylphenyl)amino]-1H- benzimidazol-5-yl}oxy)pyridine-2-carboxamide 458.3 1396

4-[(2-{[3-(2-furyl)-4-methylphenyl]- amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carbox- amide 454.3 1397

4-[(2-{[4-chloro-3-(3-furyl)phenyl]- amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carbox- amide 474.3 1398

4-[(2-{[4-fluoro-3-(3-furyl)phenyl]- amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carbox- amide 458.3 1399

4-({2-[(4-fluoro-3-tetrahydrofuran-3- ylphenyl)amino]-1-methyl-1H-benz-imidazol-5-y1}oxy)-N-methylpyridine-2- carboxamide 462.3 1400

4-({2-[(4-fluoro-3-tetrahydrofuran-2- ylphenyl)amino]-1-methyl-1H-benz-imidazol-5-yi}oxy)-N-methylpyridine-2- carboxamide 462.3

EXAMPLE 1401 Raf/Mek Filtration Assay

[0787] Buffers Assay buffer: 50 mM Tris, pH 7.5, 15 mM MgCl₂, 0.1 mMEDTA, 1 mM DTT Wash buffer: 25 mM Hepes, pH 7.4, 50 mM sodiumpyrophosphate, 500 mM NaCl Stop reagent: 30 mM EDTA Materials Raf,active: Upstate Biotech #14-352 Mek, inactive: Upstate Biotech #14-205³³P-ATP: NEN Perkin Elmer #NEG 602 h 96 well assay plates: FalconU-bottom polypropylene plates #35-1190 Filter apparatus: Millipore #MAVM096 OR 96 well filtration plates: Millipore Immobilon 1 #MAIP NOBScintillation fluid: Wallac OptiPhase “SuperMix” #1200-439 Assayconditions Raf approximately 120 pM Mek approximately 60 nM ³³P-ATP 100nM Reaction time 45-60 minutes at room temperature Assay protocol

[0788] Raf and Mek were combined at 2× final concentrations in assaybuffer (50 mM Tris, pH 7.5, 15 mM MgCl₂. 0.1 mM EDTA and 1 mM DTT) anddispensed 15 μl per well in polypropylene assay plates (Falcon U-bottompolypropylene 96 well assay plates #35-1190. Background levels aredetermined in wells containing Mek and DMSO without Raf.

[0789] To the Raf/Mek containing wells was added 3 μl of 10× of a rafkinase inhibitor test compound diluted in 100% DMSO. The raf kinaseactivity reaction was started by the addition of 12 μl per well of 2.5×³³P-ATP diluted in assay buffer. After 45-60 minutes, the reactions werestopped with the addition of 70 μl of stop reagent (30 mM EDTA).Filtration plates were pre-wetted for 5 min with 70% ethanol, and thenrinsed by filtration with wash buffer. Samples (90 μl) from the reactionwells were then transferred to the filtration plates. The filtrationplates were washed 6× with wash buffer using Millipore filtrationapparatus. The plates were dried and 100 μl per well of scintillationfluid (Wallac OptiPhase “SuperMix” #1200-439) was added. The CPM is thendetermined using a Wallac Microbeta 1450 reader.

EXAMPLE 1402 Assay 2: Biotinylated Raf Screen

[0790] In Vitro Raf Screen

[0791] The activity of various isoforms of Raf serine/threonine kinasescan be measured by providing ATP, MEK substrate, and assaying thetransfer of phosphate moiety to the MEK residue. Recombinant isoforms ofRaf were obtained by purification from sf9 insect cells infected with ahuman Raf recombinant baculovirus expression vector. Recombinant kinaseinactive MEK was expressed in E. coli and labeled with Biotin postpurification. For each assay, test compounds were serially diluted inDMSO then mixed with Raf (0.50 nM) and kinase inactive biotin-MEK (50nM) in reaction buffer plus ATP (1 μM). Reactions were subsequentlyincubated for 2 hours at room temperature and stopped by the addition of0.5 M EDTA. Stopped reaction mixture was transferred to aneutradavin-coated plate (Pierce) and incubated for 1 hour.Phosphorylated product was measured with the DELFIA time-resolvedfluorescence system (Wallac), using a rabbit anti-p-MEK (Cell Signaling)as the primary antibody and europium labeled anti-rabbit as thesecondary antibody. Time resolved fluorescence was read on a Wallac 1232DELFIA fluorometer. The concentration of each compound for 50%inhibition (IC₅₀) was calculated by non-linear regression using XL Fitdata analysis software.

[0792] Using the procedures of Examples 1116 or 1117, the compounds ofExamples 1-1094 were shown to have a raf kinase inhibitory activity atan IC₅₀ of less than 5 μM.

[0793] While the preferred embodiment of the invention has beenillustrated and described, it will be appreciated that various changescan be made therein without departing from the spirit and scope of theinvention.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:
 1. A compound of theformula (I):

wherein, X₁ and X₂ are independently selected from ═N—, —NR₄—, —O— or—S—, provided that if X₁ is —NR₄—, —O— or —S—, then X₂ is ═N—, or if X₂is —NR₄—, —O— or —S—, then X₂ is ═N—, and both X₁ and X₂ are not ═N—; Yis O or S; A₁ is substituted or unsubstituted alkyl, cycloalkyl,heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl,heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl,cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,biarylalkyl, or heteroarylarylalkyl; A₂ is substituted or unsubstitutedheteroaryl; R₁ is O or H, and R₂ is NR₅ R₆ or hydroxyl; or R₁ is takentogether with R₂ to form a substituted or unsubstituted heterocycloalkylor heteroaryl group; wherein, the dashed line represents a single ordouble bond; R₃ is hydrogen, halogen, loweralkyl, or loweralkoxy; R₄ ishydrogen, hydroxyl, alkylamino, dialkylamino or alkyl; R₅ and R6 areindependently selected from hydrogen, and substituted or unsubstitutedalkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, andheteroarylalkyl; or R₅ and R₆ are taken together to form substituted orunsubstituted heterocyclo or heteroaryl; and R₇ is loweralkyl; or apharmaceutically acceptable salt, ester or prodrug thereof.
 2. Acompound of claim 1 wherein X is NR₄.
 3. A compound of claim 2 whereinR₄ is hydrogen.
 4. A compound of claim 2 wherein R₄ is methyl.
 5. Acompound of claim 1 wherein Y is O.
 6. A compound of claim 1 wherein A₁is selected from the group consisting of substituted or unsubstitutedphenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl,pyrimidinylalkyl, heterocyclocarbonylphenyl, heterocyclophenyl,heterocycloalkylphenyl, chlorophenyl, flourophenyl, bromophenyl,iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl, 4-chlorophenyl,alkylbenzoate, alkoxyphenyl, dialkoxyphenyl, dialkylphenyl,trialkylphenyl, thiophene, thiophene-2-carboxylate, alkylthiophenyl,trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl,cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl,alkylchlorophenyl, alkylflourophenyl, triflouromethylchlorophenyl,triflouromethylbromophenyl indenyl, 2,3-dihydroindenyl, tetralinyl,triflourophenyl, (triflouromethyl)thiophenyl, alkoxybiphenyl,morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl,cyclohexylalkyl, indolyl, 2,3-dihydroindolyl,1-aceytl-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl,hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin-1-yl,pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl,adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl,imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone,anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl,phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl,piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl,pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl,N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl,hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl,1,4′-bipiperidin-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl.
 7. Acompound of claim 1 wherein A₂ is substituted or unsubstituted pyridyl.8. A compound of claim 1 wherein R₁ is O and the dashed line representsa single or double bond.
 9. A compound of claim 1 wherein R₂ is NR₅R₆,R₅ is hydrogen and R₆ is selected from hydrogen, and substituted orunsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkyloxyalkylheterocyclo, and heteroarylalkyl.
 10. A compound of claim 1wherein R₁ is taken together with R₂ to form a substituted orunsubstituted heterocycloalkyl or heteroaryl group.
 11. A compound ofclaim 1 wherein R₃ is loweralkoxy.
 12. A compound of claim 11 wherein R₃is methoxy.
 13. A compound of claim 1 wherein R₄ is loweralkyl.
 14. Acompound of claim 13 wherein R₄ is methyl.
 15. The compound of claim 1wherein R₁ is O, R₂ is NR₅R₆, R₅ is H, and R₆ is methyl.
 16. A compoundof the formula (II):

wherein and Y is O or S; A₁ is substituted or unsubstituted cycloalkyl,heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl,heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl,cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,biarylalkyl, heteroarylarylalkyl; A₂ is substituted or unsubstitutedheteroaryl; R₁ is O and R₂ is NR₅ R₆; or R₁ is taken together with R₂ toform a substituted or unsubstituted heterocycloalkyl or heteroarylgroup; wherein, the dashed line represents a single or double bond; R₃is hydrogen, halogen, loweralkyl, or loweralkoxy; R₄ is hydrogen orloweralkyl; R₅ and R₆ are independently selected from hydrogen, andsubstituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl,acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkyloxyalkylheterocyclo, and heteroarylalkyl; or R5 and R6 are takentogether to form substituted or unsubstituted heterocyclo or heteroaryl;or a pharmaceutically acceptable salt, ester or prodrug thereof.
 17. Acompound of claim 16 wherein R4 is hydrogen.
 18. A compound of claim 16wherein R4 is methyl.
 19. A compound of claim 16 wherein Y is O.
 20. Acompound of claim 16 wherein A₁ is selected from the group consisting ofsubstituted or unsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl,pyridylalkyl, pyrimidinylalkyl, heterocyclocarbonylphenyl,heterocyclophenyl, heterocycloalkylphenyl, chlorophenyl, flourophenyl,bromophenyl, iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl,4-chlorophenyl, alkylbenzoate, alkoxyphenyl, dialkoxyphenyl,dialkylphenyl, trialkylphenyl, thiophene, thiophene-2-carboxylate,alkylthiophenyl, trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl,biphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl,alkylbromophenyl, alkylchlorophenyl, alkylflourophenyl,triflouromethylchlorophenyl, triflouromethylbromophenyl indenyl,2,3-dihydroindenyl, tetralinyl, triflourophenyl,(triflouromethyl)thiophenyl, alkoxybiphenyl, morpholinyl, N-piperazinyl,N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl,2,3-dihydroindolyl, 1-aceytl-2,3-dihydroindolyl, cycloheptyl,bicyclo[2.2.1]hept-2-yl, hydroxyphenyl, hydroxyalkylphenyl,pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-1-ylalkyl,4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl,bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl,imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone,anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl,phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl,piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl,pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl,N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl,hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl,1,4′-bipiperidin-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl. 21.A compound of claim 16 wherein A₂ is substituted or unsubstitutedpyridyl.
 22. A compound of claim 16 wherein R₁ is O and the dashed linerepresents a single or double bond.
 23. A compound of claim 16 whereinR₂ is NR₅R₆, R₅ is hydrogen and R₆ is selected from hydrogen, andsubstituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl,acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkyloxyalkylheterocyclo, and heteroarylalkyl.
 24. A compound of claim16 wherein R₁ is taken together with R₂ to form a substituted orunsubstituted heterocycloalkyl or heteroaryl group.
 25. A compound ofclaim 16 wherein R₁ is O, R₂ is NR₅R₆, R₅ is H, and R₆ is methyl.
 26. Acompound of claim 16 wherein R₃ is loweralkoxy.
 27. A compound of claim26 wherein R₃ is methoxy.
 28. A compound of claim 16 wherein R₄ isloweralkyl.
 29. A compound of claim 28 wherein R₄ is methyl.
 30. Acompound of the formula (III):

wherein X is NR₄, O or S; A₁ is substituted or unsubstituted cycloalkyl,heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl,heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl,cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,biarylalkyl, heteroarylarylalkyl; A₂ is substituted or unsubstitutedheteroaryl; R₁ is O and R₂ is NR₅ R₆; or R₁ is taken together with R₂ toform a substituted or unsubstituted heterocycloalkyl or heteroarylgroup; wherein, the dashed line represents a single or double bond; R₃is hydrogen, halogen, loweralkyl, or loweralkoxy; R₄ is hydrogen orloweralkyl; R₅ and R₆ are independently selected from hydrogen, andsubstituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl,acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkyloxyalkylheterocyclo, and heteroarylalkyl; or R5 and R6 are takentogether to form substituted or unsubstituted heterocyclo or heteroaryl;or a pharmaceutically acceptable salt, ester or prodrug thereof.
 31. Acompound of claim 30 wherein X is NR₄.
 32. A compound of claim 31wherein R₄ is hydrogen.
 33. A compound of claim 30 wherein R₄ is methyl.34. A compound of claim 30 wherein A₁ is selected from the groupconsisting of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl,phenylalkyl, pyridylalkyl, pyrimidinylalkyl, heterocyclocarbonylphenyl,heterocyclophenyl, heterocycloalkylphenyl, chlorophenyl, flourophenyl,bromophenyl, iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl,4-chlorophenyl, alkylbenzoate, alkoxyphenyl, dialkoxyphenyl,dialkylphenyl, trialkylphenyl, thiophene, thiophene-2-carboxylate,alkylthiophenyl, trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl,biphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl,alkylbromophenyl, alkylchlorophenyl, alkylflourophenyl,triflouromethylchlorophenyl, triflouromethylbromophenyl indenyl,2,3-dihydroindenyl, tetralinyl, triflourophenyl,(triflouromethyl)thiophenyl, alkoxybiphenyl, morpholinyl, N-piperazinyl,N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl,2,3-dihydroindolyl, 1-aceytl-2,3-dihydroindolyl, cycloheptyl,bicyclo[2.2.1]hept-2-yl, hydroxyphenyl, hydroxyalkylphenyl,pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-1-ylalkyl,4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl,bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl,imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone,anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl,phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl,piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl,pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl,N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl,hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl,1,4′-bipiperidin-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl. 35.A compound of claim 30 wherein A₂ is substituted or unsubstitutedpyridyl.
 36. A compound of claim 30 wherein R₁ is O and the dashed linerepresents a single or double bond.
 37. A compound of claim 30 whereinR₂ is NR₅R₆, R₅ is hydrogen and R₆ is selected from hydrogen, andsubstituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl,acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkyloxyalkylheterocyclo, and heteroarylalkyl.
 38. A compound of claim30 wherein R₁ is taken together with R₂ to form a substituted orunsubstituted heterocycloalkyl or heteroaryl group.
 39. A compound ofclaim 30 wherein R₃ is loweralkoxy.
 40. A compound of claim 39 whereinR₃ is methoxy.
 41. A compound of claim 30 wherein R₄ is loweralkyl. 42.A compound of claim 41 wherein R₄ is methyl.
 43. A compound of claim 30wherein R₁ is O, R₂ is NR₅R₆, R₅ is H, and R₆ is methyl.
 44. A compoundof the formula (IV):

wherein X is NR₄, O or S; Y is O or S; A₁ is substituted orunsubstituted cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl,polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl,heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,heteroarylalkyl, biarylalkyl, heteroarylarylalkyl; R₁ is O and R₂ is NR₅R₆; or R₁ is taken together with R₂ to form a substituted orunsubstituted heterocycloalkyl or heteroaryl group; wherein, the dashedline represents a single or double bond; R₃ is hydrogen, halogen,loweralkyl, or loweralkoxy; R₄ is hydrogen or loweralkyl; R₅ and R₆ areindependently selected from hydrogen, and substituted or unsubstitutedalkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, andheteroarylalkyl; or R5 and R6 are taken together to form substituted orunsubstituted heterocyclo or heteroaryl; or a pharmaceuticallyacceptable salt, ester or prodrug thereof.
 45. A compound of claim 44wherein X is NR₄.
 46. A compound of claim 45 wherein R₄ is hydrogen. 47.A compound of claim 45 wherein R₄ is methyl.
 48. A compound of claim 44wherein Y is O.
 49. A compound of claim 44 wherein A₁ is selected fromthe group consisting of substituted or unsubstituted phenyl, pyridyl,pyrimidinyl, phenylalkyl, pyridylalkyl, pyrimidinylalkyl,heterocyclocarbonylphenyl, heterocyclophenyl, heterocycloalkylphenyl,chlorophenyl, flourophenyl, bromophenyl, iodophenyl, dihalophenyl,nitrophenyl, 4-bromophenyl, 4-chlorophenyl, alkylbenzoate, alkoxyphenyl,dialkoxyphenyl, dialkylphenyl, trialkylphenyl, thiophene,thiophene-2-carboxylate, alkylthiophenyl, trifluoromethylphenyl,acetylphenyl, sulfamoylphenyl, biphenyl, cyclohexylphenyl,phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl,alkylchlorophenyl, alkylflourophenyl, triflouromethylchlorophenyl,triflouromethylbromophenyl indenyl, 2,3-dihydroindenyl, tetralinyl,triflourophenyl, (triflouromethyl)thiophenyl, alkoxybiphenyl,morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl,cyclohexylalkyl, indolyl, 2,3-dihydroindolyl,1-aceytl-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl,hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin-1-yl,pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl,adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl,imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone,anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl,phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl,piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl,pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl,N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl,hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl,1,4′-bipiperidin-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl. 50.A compound of claim 44 wherein R₁ is O and the dashed line represents asingle or double bond.
 51. A compound of claim 44 wherein R₂ is NR₅R₆,R₅ is hydrogen and R₆ is selected from hydrogen, and substituted orunsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkyloxyalkylheterocyclo, and heteroarylalkyl.
 52. A compound of claim44 wherein R₁ is taken together with R₂ to form a substituted orunsubstituted heterocycloalkyl or heteroaryl group.
 53. A compound ofclaim 44 wherein R₃ is loweralkoxy.
 54. A compound of claim 53 whereinR₃ is methoxy.
 55. A compound of claim 44 wherein R₄ is loweralkyl. 56.A compound of claim 55 wherein R₄ is methyl.
 57. A compound of claim 44wherein R₁ is O, R₂ is NR₅R6, R₅ is H, and R₆ is methyl.
 58. A compoundof the formula (V):

wherein X is NR₄, O or S; A₁ is substituted or unsubstituted cycloalkyl,heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl,heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl,cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,biarylalkyl, heteroarylarylalkyl; R₁ is O and R₂ is NR₅ R₆; or R₁ istaken together with R₂ to form a substituted or unsubstitutedheterocycloalkyl or heteroaryl group; wherein, the dashed linerepresents a single or double bond; R₃ is hydrogen, halogen, loweralkyl,or loweralkoxy; R₄ is hydrogen or loweralkyl; R₅ and R₆ areindependently selected from hydrogen, and substituted or unsubstitutedalkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, andheteroarylalkyl; or R5 and R6 are taken together to form substituted orunsubstituted heterocyclo or heteroaryl; or a pharmaceuticallyacceptable salt, ester or prodrug thereof.
 59. A compound of claim 58wherein X is NR₄.
 60. A compound of claim 59 wherein R₄ is hydrogen. 61.A compound of claim 59 wherein R₄ is methyl.
 62. A compound of claim 58wherein A₁ is selected from the group consisting of substituted orunsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl,pyrimidinylalkyl, heterocyclocarbonylphenyl, heterocyclophenyl,heterocycloalkylphenyl, chlorophenyl, flourophenyl, bromophenyl,iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl, 4-chlorophenyl,alkylbenzoate, alkoxyphenyl, dialkoxyphenyl, dialkylphenyl,trialkylphenyl, thiophene, thiophene-2-carboxylate, alkylthiophenyl,trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl,cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl,alkylchlorophenyl, alkylflourophenyl, triflouromethylchlorophenyl,triflouromethylbromophenyl indenyl, 2,3-dihydroindenyl, tetralinyl,triflourophenyl, (triflouromethyl)thiophenyl, alkoxybiphenyl,morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl,cyclohexylalkyl, indolyl, 2,3-dihydroindolyl,1-aceytl-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl,hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin-1-yl,pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl,adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl,imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone,anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl,phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl,piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl,pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl,N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl,hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl,1,4′-bipiperidin-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl. 63.A compound of claim 58 wherein R₁ is O and the dashed line represents asingle or double bond.
 64. A compound of claim 58 wherein R₂ is NR₅R₆,R₅ is hydrogen and R₆ is selected from hydrogen, and substituted orunsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkyloxyalkylheterocyclo, and heteroarylalkyl.
 65. A compound of claim58 wherein R₁ is taken together with R₂ to form a substituted orunsubstituted heterocycloalkyl or heteroaryl group.
 66. A compound ofclaim 58 wherein R₃ is loweralkoxy.
 67. A compound of claim 66 whereinR₃ is methoxy.
 68. A compound of claim 58 wherein R₄ is loweralkyl. 69.A compound of claim 68 wherein R₄ is methyl.
 70. A compound of claim 58wherein R₁ is O, R₂ is NR₅R₆, R₅ is H, and R₆ is methyl.
 71. Acomposition comprising an amount of a compound of claims 1, 16, 30, 44,or 58 effective to inhibit Raf activity in a human or animal subjectwhen administered thereto, together with a pharmaceutically acceptablecarrier.
 72. A composition of claim 71 which further comprises at leastone additional agent for the treatment of cancer.
 73. A composition ofclaim 72 in which the at least one additional agent for the treatment ofcancer is selected from irinotecan, topotecan, gemcitabine,5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes,tezacitabine, cyclophosphamide, vinca alkaloids, imatinib,anthracyclines, rituximab and trastuzumab.
 74. A method of inhibitingRaf kinase activity in a human or animal subject, comprisingadministering to the human or animal subject a composition comprising anamount of a compound of claims 1, 16, 30, 44 or 58 effective to inhibitRaf kinase activity in the human or animal subject.
 75. A method fortreating a cancer disorder in a human or animal subject, comprisingadministering to the human or animal subject a composition comprising anamount of a compound of claims 1, 16, 30, 44 or 58 effective to inhibitRaf kinase activity in the human or animal subject.
 76. A method ofclaim 75 which further comprises administering to the human or animalsubject at least one additional agent for the treatment of cancer.
 77. Amethod of claim 76 in which the at least one additional agent for thetreatment of cancer is selected from irinotecan, topotecan, gemcitabine,5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes,tezacitabine, cyclophosphamide, vinca alkaloids, imatinib,anthracyclines, rituximab and trastuzumab.
 78. A method for treating ahormone dependent cancer disorder in a human or animal subject,comprising administering to the human or animal subject a compositioncomprising an amount of a compound of claims 1, 16, 30, 44 or 58effective to inhibit Raf kinase activity in the human or animal subject.79. A method of claim 78 wherein the hormone dependent cancer is breastcancer or prostate cancer.
 80. A method of claim 78 which furthercomprises administering to the human or animal subject at least oneadditional agent for the treatment of cancer.
 81. A method of claim 80in which the at least one additional agent for the treatment of canceris selected from irinotecan, topotecan, gemcitabine, 5-fluorouracil,leucovorin carboplatin, cisplatin, taxanes, tezacitabine,cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximaband trastuzumab.
 82. A method for treating a hematological cancerdisorder in a human or animal subject, comprising administering to thehuman or animal subject a composition comprising an amount of a compoundof claims 1, 16, 30, 44 or 58 effective to inhibit Raf kinase activityin the human or animal subject.
 83. A method of claim 82 which furthercomprises administering to the human or animal subject at least oneadditional agent for the treatment of cancer.
 84. A method of claim 83in which the at least one additional agent for the treatment of canceris selected from irinotecan, topotecan, gemcitabine, 5-fluorouracil,leucovorin carboplatin, cisplatin, taxanes, tezacitabine,cyclophospharmide, vinca alkaloids, imatinib, anthracyclines, rituximaband trastuzumab.
 85. A compound of claims 1, 16, 30, 44 or 58 for use inthe treatment of cancer.
 86. Use of a compound of claims 1, 16, 30, 44or 58 in the manufacture of a medicament for the treatment of cancer.